Ketamine - Magic Antidepressant, or Expensive Illusion?

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 inactive placebo. 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

Free Will: A Dangerous Idea?

The British Journal of Social Psychology has published a fiery rebuke to psychologists who argue that belief in free will makes people more ethical.

Recent much-publicized studies have claimed that scepticism about free will makes people behave less morally. "Disbelief in Free Will Increases Aggression and Reduces Helpfulness" as the title of one of hese papers puts it.

In his article (free pdf), British 'independent researcher' James B. Miles says that these experiments are flawed, because they didn't distinguish between determinism (lack of free choice) and fatalism (lack of the ability to change events).

More fundamentally, though, Miles says that free will is used to justify things, such as punishment and poverty, that would otherwise be seen as scandalous -

Western law recognizes that the penal system is so harmful to the existing life and future opportunities of persons that to convict requires evidence beyond a reasonable doubt. Yet libertarians provide no objective evidence whatsoever for the existence of free will, and therefore no apparent justification for the mass poverty and brutal punishments that belief in libertarian free will often brings with it. The leading legal theorist Stephen J. Morse freely admits that harsh prison conditions and execution are only morally tolerable where the presumption of free choice exists...

...In June 2009, the Joseph Rowntree Foundation published research showing that up to 83% of Britons think that ‘virtually everyone’ remains in poverty in Britain not as the result of social
misfortune or biological handicap but through choice (Bamfield & Horton, 2009, p. 23; 69% of those surveyed agreed with the statement and an additional 14% were unsure but did not disagree.) Because of their belief in the fairness of ‘deserved inequalities’, such respondents were discovered to have become almost completely unconcerned with the idea of promoting greater equality while at the same time asserting that Britain was a beacon of fairness that offered opportunities for all...

...Free will may just be the primary excuse many use to legitimize a contempt for the poor that would exist independent of their professed belief in free will, but free will assertion nonetheless provides the ethical fig leaf for such contempt that would be far harder to rationalize (and therefore tolerate) without the myth of free will.

This is a polemical piece (remarkably so, for an academic journal), and clearly this is only one side of the story, but it's hard to deny that he has a point: there's a dark side to the belief in free will. If you doubt free will, and yet praise the myth of it, as some scientists seem to be doing, you need to accept that you're condemning some people (prisoners, most obviously) to suffer as a result "through no fault of their own".

Personally, I think the great majority of people do believe in free will and always will - the arguments against it have been around for millenia, they're as convincing as they'll ever be, and they haven't convinced most people, however irrational that might make most people. So I think the debate over belief in free will is academic; it's not going away.

 Miles JB (2011). 'Irresponsible and a Disservice': The integrity of social psychology turns on the free will dilemma. The British journal of social psychology / the British Psychological Society PMID: 22074173

The World Mental Health Missionaries?

Is research on the global distribution of mental health problems a kind of modern-day missionary work?

Maybe, says Australia's Dr Stephen Rosenman in a provocative paper: Cause for caution: culture,sensitivity and the World Mental Health Survey Initiative.

The World Mental Health Survey (WMHS) is a huge World Health Organization project that aims to measure the rates of various psychiatric disorders in countries around the world. The WMHS has produced a great deal of data, but Rosenman points out that this assumes that people all over the world suffer from the same psychiatric disorders (and display them in the same ways) as the Americans and Europeans about whom the diagnostic manual was originally written.

The surveys translated the diagnostic criteria into the local languages, of course, but that doesn't mean they were appropriate to the local cultures.

He suggests that all this is a bit like missionaries who went around translating the Bible and trying to convince people to read it -

Looked at with a less admiring eye, the [WMHS] resembles in some ways the missionary movements of the last two centuries. Like the missionaries, the organisers are committed, selfless people of extraordinary goodwill who have come to poor countries from cultures at the apogee of their wealth, prestige and intellectual power.

They bring an evolved and highly developed system of thought. They set about delivering the fruits of that to the people. The survey initiative has engaged the leaders of the profession in the countries and, in a sense, has converted them to this view of psychopathology.

It is difficult to know if their success is due to the power of the ideas they brought, or the power and prestige of the cultures they came from, or from their technique of taking over both the centre and the contours of the beliefs of a culture. Missionaries brought a ‘colonisation of consciousness’... etc.

He does goes on to say though, "I do not want to push the missionary analogy too far" which is wise I think; there are important differences and other analogies are equally apt.

The paper's a good read though. It refers to Crazy Like Us, a book I'm fond of.

Although Rosenman doesn't cite another important source (cough cough): he points out that the WMHS national estimates of rates of depression don't correlate at all with national suicide rates, which is seriously odd -

According to the CIDI [the psychiatric interview used in the WMHS], Japan, for example, has one-third the rate of mood disorders (3.1%) seen in the USA (9.6%). At the same time, Japan’s suicide rate (20.3/100,000) is twice that of the USA (10.8/100,000). Suicide rates seem to have almost no relationship with CIDI diagnoses of affective disorder... Suicide, of course, is complexly shaped by the culture but are we to believe that answers to the CIDI are any less culturally determined and which is to be considered the better index of disorder?

I made the very same point using the very same datasets in 2009 (although I looked at 'all mental illness' rather than 'mood disorders').

Rosenman, S. (2012). Cause for caution: culture, sensitivity and the World Mental Health Survey Initiative Australasian Psychiatry, 20 (1), 14-19 DOI: 10.1177/1039856211430149

WAFFLE: Why Most Books Are Too Long

I have a theory about modern books.

There's a certain kind of book, let's call it the "TITLE: How This Subtitle Summarizes My Big Idea" genre.

I don't think I need to name names.

Now, I read a lot of these, and I've come to the conclusion that most of these books shouldn't books at all. That's not to say they're bad - the big idea may be brilliant, but I don't care how big your idea is, you do not need 100-200 pages to explain one idea.

They tend to contain a couple of core chapters with the good stuff and maybe 4 or 5 chapters of what can best be called waffle. Anecdotes, backstory, additional illustrations, etc. Like a waffle this may be perfectly pleasant - but it's not very nutritious.

Here's why I think this is - publishers (we are told) increasingly want books with a single big idea that can be summed up in a sentence. Partly because they sell, and partly because publishers are overstretched and just don't have time themselves to spend hours thinking through a complex argument to find out if it's any good.

But the problem is that, for whatever historical and business reasons, books are meant to be a certain length, say 100 pages bare minimum. No-one prints 50 page books and few people would buy one, except children etc.

So there's a gap in the profile of the length of non-fiction writing. There are all kinds of shortish pieces - from the briefest news reports and op-eds up to long feature articles and New York Review of Books type articles. That covers all the way from 1 to up to, say, 10,000 words.

But then there's nothing until you reach the short book at (say) 35,000 words, after which, it's plain sailing again.

Think about it - have you ever read a 20,000 word piece of non-fiction? I don't think I have. It's too long for a periodical but too short to be a book. (Academic papers are an exception; I'm thinking of general interest pieces).

Yet it seems to me that a great many of today's books could have been that length, without weakening the argument or dumbing down in any way. And, if so, then they should be, because a fundamental rule of good writing is to keep things as concise as possible. The problem is that while that would make them better as pieces of writing, it would make them unmarketable as books, or anything else; there's practically no market for 20,000 good words and true.

Except... now we have ebooks.

So you could see this post as an argument in praise of ebooks, not just as a new technology but as a whole new form of writing falling somewhere between the "article" and the "book". Which is ironic because I don't even have a Kindle yet. Of course I'm not saying that all books are too long. I like books. Many are the right length, some I wish were longer; but just because an idea could be made into a book, doesn't mean it should be.

Edit: I hadn't read this when I wrote this post but it seems the industry are way ahead of me -

Yesterday, Amazon began selling its Kindle Singles online. Singles are e-books between 5,000 and 30,000 words long. According to the press release, these e-books are meant to “allow a single killer idea — well researched, well argued and well illustrated — to be expressed at its natural length.”

Bringing the Real World into Brain Scanning

Canadian Neuroscientists Jacqueline Snow et al propose a new method of making brain scanning studies a bit more realistic.

Typically, in an fMRI or other neuroimaging study, any visual stimuli shown to the volunteer are just pictures on a screen. Sometimes videos will be used, but in almost all cases they're just 2D images. Is that adaquate? People have hoped so.

Snow et al's data suggest that it might not be.

They created a contraption for presenting subjects with real objects during a scan. See above. Now, to the uninitiated this might not seem like a big deal, but those with MRI experience will appreciate how impressive this is.

Everything from the angle of the volunteer's head to the LED lighting is an achivement, given the nature of MRI. The stimuli were controlled by one of the researchers, who had to sit next to the scanner, in total darkness, and operate the turntable with the help of some glow-in-the-dark stickers.

Having built this device, they then used it to compare the brain's responses to real objects vs photos of those same objects. The experiment was designed to test fMRI adaptation - the phenemenon whereby if you present the same stimuli repeatedly, the neural responses are reduced.

fMRI adaptation has been found to happen in many studies using 2D pictures, but Snow et al show that the effect was much smaller, maybe entirely absent, when people were repeatedly shown real objects: this graph shows the BOLD neural response in the lateral occipital complex. Seeing the same pictures over and over led to a weaker response, as expected; but seeing the same 3D objects didn't:

This is a good study and an important result, which suggests that the much-studied fMRI adaptation might not be a universal phenemonon. And the potential implications are big, as the authors write:

Finally, our preliminary fMRI results raise the provocative suggestion that the presence of real-world objects (i.e., as indicated initially via stereoscopic cues) invokes qualitatively different computations to those elicited by 2D images. Researchers in the field of behavioral psychophysics have expressed long-standing concern about the extent to which pictures of objects capture the properties of their real-world counterparts (i.e., their ecological validity), with reservations as to their appropriateness as stimuli with which to examine the nature of human object perception...

Snow, J., Pettypiece, C., McAdam, T., McLean, A., Stroman, P., Goodale, M., and Culham, J. (2011). Bringing the real world into the fMRI scanner: Repetition effects for pictures versus real objects Scientific Reports, 1 DOI: 10.1038/srep00130