Nature has a disturbing article from their Asian correspondent David Cyranoski: Thought experiment. It's open access.

In brief: a number of top Japanese psychiatrists have started offering a neuroimaging method called NIRS to their patients as a diagnostic tool. They claim that NIRS shows the neural signatures of different mental illnesses.

The technology was approved by the Japanese authorities in April 2009, and since then it's been used on at least 300 patients, who pay $160 for the privilege. However, it's not clear that it works.

To put it mildly.

• Matsuo et al (2000) n=9/10 elderly depressed/controls
• Suto et al (2004) n=10/13/16 depressed/schizophrenia/controls
• Kameyama et al (2006) n=17/11/17 bipolar/depression/controls
• Nishimura et al (2007) n=5/33 panic disorder/controls
• Takizawa et al (2008) n=55/70 schizophrenia/controls
• Uehara et al (2007) n=11/11 eating disorder/controls
• Suda et al (2010) n=27/27 eating disorder/controls

...when Fukuda calculates his success rates, NIRS results that match the clinical diagnosis are considered a success. If the results don’t match, Fukuda says he will ask the patient and patient’s family “repeatedly” whether they might have missed something — for example, whether a depressed patient whose NIRS examination suggests schizophrenia might have forgotten to mention that he was experiencing hallucinations.

Back in 2009, a crack team of neuroscientists led by Craig Bennett (blog) famously put a dead fish into an MRI scanner and showed it some pictures.



They found some blobs of activation - when they used an inappropriately lenient statistical method. Their point, of course, was to draw attention to the fact that you really shouldn't use that method for fMRI. You can read the whole paper here. The Atlantic Salmon who heroically volunteered for the study was no more than a prop. In fact, I believe he ended up getting eaten.

But now, a Japanese team have just published a serious paper which actually used fMRI to measure brain activity in some salmon: Olfactory Responses to Natal Stream Water in Sockeye Salmon by BOLD fMRI.

How do you scan a fish? Well, like this:

A total of 6 fish were scanned. The salmon were immobilized by adding an anaesthetic (eugenol) and a muscle relaxant (gallamine) to their tank of water. Then, they were carefully clamped into place to make sure they really wouldn't move, while a stream of oxygenated water was pumped through their tank.

Apart from that, it was pretty much a routine fMRI scan.

Why would you want to scan a fish? This is where the serious science comes in. Salmon are born in rivers but they swim out to live in the ocean once they reach maturity. However, they return to the river to breed. What's amazing is that salmon will return to the same river that they were born in - even if they have to travel thousands of miles to get there.

How they manage this is unclear, but the smell (or maybe taste) of the water from their birth river has long been known to be crucial at least once they've reached the right general area (see here for a good overview). Every river contains a unique mixture of chemicals, both natural and artificial (pollutants). Salmon seem to be attracted to whatever chemicals were present in the water when they were young.

In this study, the fMRI revealed that relative to pure water, home-stream water activated a part of the salmon's telencephalon - the most "advanced" part (in humans, it constitutes the vast majority of the brain; in fish, it's tiny). By contrast, a control scent (the amino acid L-serine) did not activate this area, even though the concentration of L-serine was far higher than that of anything in the home-stream water. How this happens is unclear, but further studies of the identified telencephalon area ought to shed more light on it.

So fishMRI is clearly a fast-developing area of neuroscience. In fact, as this graph shows, it's enjoying exponential growth and, if current trends continue, could become almost as popular as scanning people...

Link: Also blogged at NeuroDojo.

There's a lot of talk, much of it rather speculative, about "neuroethics" nowadays.

But there's one all too real ethical dilemma, a direct consequence of modern neuroscience, that gets very little attention. This is the problem of incidental findings on MRI scans.

An "incidental finding" is when you scan someone's brain for research purposes, and, unexpectedly, notice that something looks wrong with it. This is surprisingly common: estimates range from 2–8% of the general population. It will happen to you if you regularly use MRI or fMRI for research purposes, and when it does, it's a shock. Especially when the brain in question belongs to someone you know. Friends, family and colleagues are often the first to be recruited for MRI studies.

This is why it's vital to have a system in place for dealing with incidental findings. Any responsible MRI scanning centre will have one, and as a researcher you ought to be familiar with it. But what system is best?

Broadly speaking there are two extreme positions:

1. Research scans are not designed for diagnosis, and 99% of MRI researchers are not qualified to make a diagnosis. What looks "abnormal" to Joe Neuroscientist BSc or even Dr Bob Psychiatrist is rarely a sign of illness, and likewise they can easily miss real diseases. So, we should ignore incidental findings, pretend the scan never happened, because for all clinical purposes, it didn't.
2. You have to do whatever you can with an incidental finding. You have the scans, like it or not, and if you ignore them, you're putting lives at risk. No, they're not clinical scans, they can still detect many diseases. So all scans should be examined by a qualified neuroradiologist, and any abnormalities which are possibly pathological should be followed-up.

Should a dodgy paper on antidepressants be retracted? And what's scientific retraction for, anyway?


Read all about it in a new article in the BMJ: Rules of Retraction. It's about the efforts of two academics, Jon Jureidini and Leemon McHenry. Their mission - so far unsuccesful - is to get this 2001 paper retracted: Efficacy of paroxetine in the treatment of adolescent major depression.

Jureidini is a member of Healthy Skepticism, a fantastic Australian organization that Neuroskeptic readers have encountered before. They've got lots of detail on the ill-fated "Study 329", including internal drug company documents, here.

So what's the story? Study 329 was a placebo-controlled trial of the SSRI paroxetine (Paxil, Seroxat) in 275 depressed adolescents. The paper concluded: that "Paroxetine is generally well tolerated and effective for major depression in adolescents." It was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP).

There's two issues here: whether paroxetine worked, and whether it was safe. On safety, the paper concluded that "Paroxetine was generally well tolerated...and most adverse effects were not serious." Technically true, but only because there were so many mild side effects.

In fact, 11 patients on paroxetine reported serious adverse events, including suicidal ideation or behaviour, and 7 were hospitalized. Just 2 patients in the placebo group had such events. Yet we are reassured that "Of the 11, only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment."

The drug company argue that it didn't become clear that paroxetine caused suicidal ideation in adolescents until after the paper was published. In 2002, British authorities reviewed the evidence and said that paroxetine should not be given in this age group.

That's as maybe; the fact remains that in this paper there was a strongly raised risk. However, in fairness, all that data was there in the paper, for readers to draw their own conclusions from. The paper downplays it, but the numbers are there.

Study 329’s results showed that paroxetine was no more effective than the placebo according to measurements of eight outcomes specified by Martin Keller, professor of psychiatry at Brown University, when he first drew up the trial.

Two of these were primary outcomes...the drug also showed no significant effect for the initial six secondary outcome measures. [it] only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used... Fifteen other new secondary outcome measures failed to throw up positive results.

Of the depression-related variables, paroxetine separated statistically from placebo at endpoint among four of the parameters: response (i.e., primary outcome measure)...

Many of the best things in life are terrible.


We all know about the fun to be found in failure, as exemplified by Judge A Book By Its Cover and of course FailBlog. The whole genre of B-movie appreciation is based on the maxim of: so bad, it's good.

But could the same thing apply to psychotherapies?

Here's the argument. Freudian psychoanalysis is a bit silly. Freud had pretensions to scientific respectability, but never really achieved it, and with good reason. You can believe Freud, and if you do, it kind of make sense. But to anyone else, it's a bit weird. If psychoanalysis were a person, it would be the Pope.

By contrast, cognitive-behavioural therapy is eminently reasonable. It relies on straightforward empirical observations of the patient's symptoms, and on trying to change people's beliefs by rational arguments and real-life examples ("behavioural experiments"). CBT practitioners are always keen to do randomized controlled trials to provide hard evidence for their success. CBT is Richard Dawkins.

But what if the very irrationality of psychoanalysis is its strength? Mental illness is irrational. So's life, right? So maybe you need an irrational kind of therapy to deal with it.

This is almost the argument advanced by Robert Rowland Smith in a short piece In Defence of Psychoanalysis:

...The irony is that in becoming more “scientific”, CBT becomes less therapeutic. Now, Freud himself liked to be thought of as a scientist (he began his career in neurology, working on the spinal ganglia), but it’s the non-scientific features that make psychoanalysis the more, not the less, powerful.

I’m referring to the therapeutic relationship itself. Although like psychoanalysis largely a talking cure, CBT prefers to set aside the emotions in play between doctor and patient. Psychoanalysis does the reverse. To the annoyance no doubt of many a psychoanalytic patient, the very interaction between the two becomes the subject-matter of the therapy.

The respected therapist and writer Irvin Yalom, among others, argues that depression and associated forms of sadness stem from an inability to make good contact with others. Relationships are fundamental to happiness. And so a science that has the courage to include the doctor’s relationship with the patient within the treatment itself, and to work with it, is a science already modelling the solution it prescribes. What psychoanalysis loses in scientific stature, it gains in humanity.

Does being heavier make you happier?

An interesting new paper from a British/Danish collaboration uses a clever trick based on genetics to untangle the messy correlation between obesity and mental health.

They had a huge (53,221) sample of people from Copenhagen, Denmark. It measured people's height and weight to calculate their BMI, and asked them some simple questions about their mood, such as "Do you often feel nervous or stressed?"

Many previous studies have found that being overweight is correlated with poor mental health, or at least with unhappiness ("psychological distress"). And this was exactly what the authors found in this study, as well.

Being very underweight was also correlated with distress; perhaps these were people with eating disorders or serious medical illnesses. But if you set those small number of people aside, there was a nice linear correlation between BMI and unhappiness. When they controlled for various other variables like income, age, and smoking, the effect of BMI became smaller but it was still significant.

But that's just a correlation, and as we all know, "correlation doesn't imply causation". Actually, it does; something must be causing the correlation, it didn't just magically appear out of nowhere. The point is that shouldn't make simplistic assumptions about what the causal direction is.

It would be easy to make these assumptions. Maybe being miserable makes you fat, due to comfort eating. Or maybe being fat makes you miserable, because overweight is considered bad in our society. Or both. Or neither. We don't know.

Finding this kind of correlation and then speculating about it is where a lot of papers finish, but for these authors, it was just the start. They genotyped everyone for two different genetic variants known, from lots of earlier work, to consistently affect body weight (FTO rs9939609 and MC4R rs17782313).

They confirmed that they were indeed associated with BMI; no surprise there. But here's the surprising bit: the "fat" variants of each gene were associated with less psychological distress. The effects were very modest, but then again, their effects on weight are small too (see the graph above; the effects are in terms of z scores and anything below 0.3 is considered "small".)

The picture was very similar for the other gene.

This allows us to narrow down the possibilities about causation. Being depressed clearly can't change your genotype. Nothing short of falling into a nuclear reactor can change your genotype. It also seems unlikely that genotype was correlated with something else which protects against depression. That's not impossible; it's the problem of population stratification, and it's a serious issue with multi-ethnic samples, but this paper only included white Danish people.

So the author's conclusion is that being slightly heavier causes you to be slightly happier, even though overall, weight is strongly correlated with being less happy. This seems paradoxical, but that's what the data show.

That conclusion would fall apart, though, if these genes directly effect mood, and also, separately, make you fatter. The authors argue that this is unlikely, but I wonder. Both FTO and MC4R are active in the brain: they influence weight by making you eat more. If they can affect appetite, they might also affect mood. A quick PubMed search only turns up a couple of rather speculative papers about MC4R and its possible links to mood, so there's no direct evidence for this, but we can't rule it out.

But this paper is still an innovative and interesting attempt to use genetics to help get beneath the surface of complex correlations. It doesn't explain the observed correlation between BMI and unhappiness - it actually makes it more mysterious. But that's a whole lot better than just speculating about it.

Lawlor DA, Harbord RM, Tybjaerg-Hansen A, Palmer TM, Zacho J, Benn M, Timpson NJ, Smith GD, & Nordestgaard BG (2011). Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults. Journal of internal medicine PMID: 21210875

A new paper has added to the growing ranks of studies finding that antidepressant drugs don't work in people with milder forms of depression: Efficacy of antidepressants and benzodiazepines in minor depression.


It's in the British Journal of Psychiatry and it's a meta-analysis of 6 randomized controlled trials on three different drugs. Antidepressants were no better than placebo in patients with "minor depressive disorder", which is like the better-known Major Depressive Disorder but... well, not as major, because you only need to have 2 symptoms instead of 5 from this list.

They also wanted to find out whether benzodiazepines (like Valium) worked in these people, but there just weren't any good studies out there.

The results look solid, and they fit with the fact that antidepressants don't work in people diagnosed with "major" depression, but who fall at the "milder" end of that range, something which several recent studies have shown. Neuroskeptic readers will, if they've been paying attention, find this entirely unsurprising.

But in fact, it's not just not news, it's positively ancient. 50 years ago, at the dawn of the antidepressant era, it was commonly said that most antidepressants don't work in everyone with "depression", they work best in people with endogenous depression, and less well, or not at all, in those with "neurotic" or "reactive" depressions (see, e.g. 1, 2, 3, but the literature goes back even further).

"Endogenous" is not strictly the same as "severe", however, in practice, these two concepts have never really been clearly seperated, and they're largely equivalent today, because the leading measure of "severity", the Hamilton Scale, measures symptoms, and arguably these symptoms are mostly (though not entirely) the symptoms of the old concept of endogenous depression. The Hamilton Scale was formulated in 1960 when modern concepts of "minor depressive disorder" and "major depressive disorder" were unknown.

Why then are we only now working out that antidepressants only work in some people? There's one obvious answer: Prozac, which arrived in 1987. Before Prozac, antidepressants were serious stuff. They could easily kill you in overdose, and they had a lot of side effects. Many of them even meant that you couldn't eat cheese. As a result, they weren't used lightly.

Prozac and the other SSRIs changed the game completely. They're much less toxic, the side effects are milder, and you can eat as much cheese as you want. So it's very easy to prescribe an SSRI - maybe it won't work, but it can't hurt, so why not try it...?

As a result, I think, the concept of "depression" broadened. Before Prozac, depression was inherently serious, because the treatments were serious. After Prozac, it didn't have to be. Drug company marketing no doubt helped this process along, but marketing has to have something to work with. Over the past 25 years, terms like "endogenous", "neurotic" etc. largely disappeared from the literature, replaced by the single construct of "Major Depression".

For nearly 1,000 years, the great scientific and philosophical work of the ancient Greeks and Romans were lost to Europeans. Only when Christian scholars rediscovered them in the libraries of the Islamic world did Europe begin to remember what it had forgotten. We call those the Dark Ages. Will the past 25 years be remembered as psychiatry's Dark Age?

Barbui, C., Cipriani, A., Patel, V., Ayuso-Mateos, J., & van Ommeren, M. (2011). Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis The British Journal of Psychiatry, 198 (1), 11-16 DOI: 10.1192/bjp.bp.109.076448

So apparently: Left wing or right wing? It's written in the brain