Another Antidepressant Bites The Dust

Yet another up-and-coming antidepressant has flopped.

A paper just out reveals that the snappily-named GSK372475 doesn't work and has lots of side effects. It's a report of two clinicals trials in which Glaxo's contender was pitched against placebo and against older antidepressants in the treatment of depression.

GSK372475 failed to improve depression any better than placebo, even though the trials were large (393 and 504 patients respectively) and twice as long as most antidepressant trials (10 weeks whereas 4 or 6 is more usual)which ought to have given it plenty of room to shine.

The comparison drugs, the widely used venlafaxine and paroxetine, did work. A bit.

One of the trials even used the Bech "Melancholia Subscale" as an outcome measure, which Neuroskeptic readers may remember as I've praised it before. Venlafaxine worked on that, GSK's new pill didn't. If anything, the new drug was worse than placebo, in that patients improved slower.

In terms of side effects it caused dry mouth, insomnia, and nausea serious enough to make many people quit the study early. But even worse, it raised heart rate by almost 10 beats per minute on average, which is really never a good sign.

So, overall, it was an utter flop. In one sense this is not surprising. New "antidepressants" that don't work in trials have been all too common recently. Just last week we learned about the failure of "Serdaxin" in a Phase II trial. Actually Serdaxin isn't a new drug but an old antibiotic called clavulanic acid that a company was trying to rebrand as a mood lifter.

However the failure of GSK372475 is a bit of a mystery. The drug is a potent triple reuptake inhibitor (TRI) which acts on the neurotransmitters serotonin, noradrenaline and dopamine. By contrast, venlafaxine is a double reuptake inhibitor which doesn't hit dopamine, and paroxetine only targets serotonin. I've written about other TRIs before.

Now it seems surprising that venlafaxine worked, but a TRI didn't, in the same trial. That would imply that blocking the reuptake of dopamine makes you more depressed, enough to cancel out the other actions which are shared with venlafaxine. Which is not what I'd have predicted.

There are other differences between the drugs though. Venlafaxine has a very short half-life - it's broken down in the body in a matter of hours. But GSK372475 has a halflife of 8-10 days. Could this be the problem?

Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, Zamuner S, Evoniuk G, & Ratti E (2011). Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials. Journal of psychopharmacology (Oxford, England) PMID: 22048884

The Transsexual Brain

According to a new paper, the brains of male-to-female transexuals are no more "female" than those of men.

The authors write that "The present data do not support the notion that brains of male-to-female transexuals are feminized" and conclude "The present study does not support the dogma that male-to-female transexuals have atypical sex dimorphism in the brain".

That last sentence has gained quite a bit of coverage, including a quote on the Wikipedia page for "transgender".

But is it so simple?

Structural MRI scans were used to compare the size of various brain structures between three groups of volunteers: heterosexual men, heterosexual women and the transexuals (or "MtF"s as I will call them for short) who were diagnosed with gender dysphoria and were "genetically and phenotypically males".

There were 24 in each group, which makes it a decent sized study. None of the MtFs had started hormone treatment yet, so that wasn't a factor, and none of the women were on hormonal contraception.

The scans showed that the non-transsexual male and female brains differed in various ways. Male brains were larger overall but women had increases in the relative volumes of various areas. Male brains were also more asymmetrical.

The key finding was that on average, the MtF brains were not like the female ones. There were some significant differences from the male brains, but they weren't the same differences that distinguished the females from the males.

This is a fairly crude approach. It looks at the groups on average. It's a finding, but there's more you could with this data. It would be better perhaps to look at the male and female groups, and then try to work out which group each individual MtF is most similar to. You could do that using a Support Vector Machine such as was previously used to detect autism.

This would also have the advantage that it would integrate the results across different brain areas: maybe the important thing is not just the size of individual areas but the relative size of one area to another area.

My real problem though is with the language used to discuss the data. The authors say that the study doesn't support "atypical sex dimorphism in the brain" yet this wasn't a study of "the brain". It was a study of one specific aspect of the brain, namely the volume of different regions. There could be all kinds of chemical and microstructural differences that don't show up on these scans.

There are lots of people with severe epilepsy, for example, whose brains clearly differ in some major way from people without epilepsy, yet they look completely normal on MRI. Only using other methods, like EEG, reveals the difference. Because the difference is chemical, not structural.

I have no idea how, or if, the brains of MtF transsexuals are "feminized" but this study doesn't rule it out. Now I'm sure the authors know all this. And in fact they themselves recently published a paper showing atypical neural responses to smelling "oderous steroids" in transsexual people. But while neuroscientists will know what they meant, I worry that studies like this could be miscontrued by other people (like Wikipedia readers) as a result of overenthusiastic language in papers.

Link: Also blogged at BPS Research Digest.

Savic I, & Arver S (2011). Sex dimorphism of the brain in male-to-female transsexuals. Cerebral cortex (New York, N.Y. : 1991), 21 (11), 2525-33 PMID: 21467211

Susan Greenfield's Dopamine Disaster

It's Susan Greenfield again.

Continuing her campaign warning of the dangers of modern technology in terms of their effects on the vulnerable brains of the young, the British neuroscientist and Baroness has written another article. This is the latest of many. None of them have been in peer reviewed academic journals.

This one's behind the Great Times Paywall so I can't link to it, but it's called Are video games taking away our identities?

The first part of the article is hard to argue against. Either you'll agree with it or you won't. Personally, videogames as Greenfield describes them bear little resemblance to any games that I've played recently. Similarly for her account of the Internet. But maybe this rings true for some:

Screen images do not depend for their impact on seeing one thing in terms of anything else. Their premium lies invariably in their raw sensory content... we are perhaps heading towards a much weaker sense of identity by engaging in a world where we are the passive recipient of senses and where there is no fixed narrative of past and future but an atomised thrill of the moment. One could even suggest that the constant self-centred readout on Twitter belies a more childlike insecurity, an existential crisis.

Greenfield then moves into discussing the brain, and this is where the science comes in. This is her "home turf" - she's Professor of physiology at Oxford. Yet it's a shambles.

There is one alarm bell ringing, which suggests that increasing 2D screen existence may be having undesirable effects: it is the threefold increase over the past decade in prescriptions for drugs for attention deficit hyperactivity disorder.

While this could be due to changes in doctors’ prescribing procedures, or indeed to a greater recognition and medicalisation of attentional problems, a third possibility could indeed be that if the young brain is exposed from the outset to a world of fast action-reaction, of instant new screen images flashing up with each press of a key, then such rapid interchange might lead to a shorter attention span.

The human condition can be basically divided into two alternating modes, first described by Euripedes... the rational “bread force”, characterised by a strong cognitive take on the world — a personalised past, present and future, in turn related to an active prefrontal cortex and lower levels of the brain chemical dopamine; and the “wine force”, more the state of young children or those adults indulging in “letting themselves go”, in situations perhaps involving wine, women and song, where a strong sensory environment demands less reflection, more passive reaction.

...An increase in physiological arousal can be linked to excessive release of dopamine. Could the screen experience be tilting this ancient balance in favour of the more infantile, senses-driven brain state?

Greenfield says that high dopamine and low prefrontal cortex activity is associated with irrationality and a deficit in attention. Video games are causing a flood of dopamine and causing ADHD. That would make sense, if ADHD was caused by too much dopamine, and if drugs for ADHD reduced dopamine release.

The problem is that it's the exact opposite. Drugs for ADHD increase dopamine release and ADHD is widely believed (although it's controversial) to be caused by a dopamine deficit.

Greenfield then says "We know too that dopamine suppresses the activity of neurons in the prefrontal cortex", but this is a serious oversimplification. Dopamine has complex effects on target neurons. It can inhibit firing, but it can also excite it. It all depends on the conditions. Here's what the authors of an influential scientific review said in 2004: "It is agreed by most researchers is that dopamine is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter"

Some say that dopamine helps to "tune" the prefrontal by increasing the signal to noise ratio - more signal, less noise. Here's one of the most cited papers about dopamine and the PFC: Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey.

Remember that drugs for ADHD like Ritalin, which are sometimes used illicitly by students without that disorder to help them focus and concentrate, cause dopamine release. If Greenfield were right, it would be the exact opposite.

...[other] people characterised by an underactive prefrontal cortex are those with schizophrenia, this time not due to physical damage but rather a chemical imbalance, in particular an excessive amount of the transmitter dopamine. In schizophrenia, like children, the patient is easily distracted, cannot interpret proverbs, is not strong on metaphor but takes the world literally; it is a vibrant world that can implode on, and overwhelm, the fragile firewall of the schizophrenic mindset.

This again is a serious simplification. Actually, you don't need to be a neuroscientist to work that out. Just recall the earlier bit: Greenfield has said that ADHD is caused by too much dopamine leading to an underactive prefrontal cortex. Now she says that schizophrenia is the same. So why are the symptoms of ADHD completely different from schizophrenia?

Why is it, in fact, that Ritalin and similar dopamine releasing drugs help with ADHD, but can make schizophrenia worse?

As a neuroscientist, I can tell you that we don't really know what's going on with dopamine in ADHD or schizophrenia. There's decent evidence that dopamine is involved in schizophrenia, but not in any straightforward sense. Schizophrenia is now believed to be linked to reduced dopamine in the prefrontal cortex, and too much in other areas.

As for ADHD, remember: the leading theory is that it's about too little dopamine. Not too much.

The only disease that we know certainly is associated with too little dopamine is Parkinson's. Contrary to Greenfield's theory, people with Parkinson's often have cognitive and mood problems as well as the better known difficulties with movements. They're not super intelligent, prefrontal-cortex-wielding geniuses.

I appreciate that an opinion piece in the Times is never going to be a rigorously argued scientific paper, but the fact that Greenfield's article contains several claims which are the exact opposite of the truth (or at least of current scientific thinking) calls her credibility into serious question.

Dream Action, Real Brain Activation

A neat little study has brought Inception one step closer to reality. The authors used fMRI to show that dreaming about doing something causes similar brain activation to actually doing it.

The authors took four guys who were all experienced lucid dreamers - able to become aware that they're dreaming, in the middle of a dream. They got them to go to sleep in an fMRI scanner. Their mission was to enter a lucid dream and move their hands in it - first their left, then their right, and so on. They also moved their eyes to signal when they were about to move their hands.

Unfortunately, only one of the intrepid dream-o-nauts succeeded, even though each was scanned more than once. Lucid dreaming isn't easy you know. Two didn't manage to enter a lucid dream. One thought he'd managed it, but the data suggested he might have actually been awake.

But one guy made it and the headline result was that his sensorimotor cortex was activated in a similar way to when he made the same movements in real life, during the lucid dream -  although less strongly. Depending on which hand he was moving in the dream, the corresponding side of the brain lit up:

EEG confirmed that he was in REM sleep and electromyography confirmed that his muscles were not in fact being activated. (During REM sleep, an inhibitory mechanism in the brain prevents muscle movement. If the EMG shows activity this is a sign that you're actually partially awake).

They also repeated the experiment with another way of measuring brain activation, NIRS. Out of five dudes, one made it. Interesting this showed the same pattern of results - weak sensorimotor cortex activation during movement - but it also showed stronger than normal supplementary motor area activation, which is responsible for planning movements.

This is rather cool but in many ways not surprising. After all, if you think about it, dreaming presumably involves all of the neural structures that are involved in really perceiving or doing whatever it is you're dreaming about. Otherwise, why would we experience it so clearly as being a dream about that thing?

It may be, however, that lucid dreaming is different, and that the motor cortex isn't activated in this way in normal dreams. I suppose it depends what the dream was about.

That raises the interesting question of what someone with brain damage would dream about. On the theory that dream experiences come from the same structures as normal experiences, you shouldn't be able to dream about something that you couldn't do in real life... I wonder if there's any data on that?

Dresler M, Koch SP, Wehrle R, Spoormaker VI, Holsboer F, Steiger A, Sämann PG, Obrig H, & Czisch M (2011). Dreamed Movement Elicits Activation in the Sensorimotor Cortex. Current biology : CB PMID: 22036177

Who Should Catch Fraud?

Whose job is it to detect scientific fraud?

You've probably heard of Diederik Stapel, a Dutch psychologist who's just admitted to scientific fraud on a grand scale, with dozens and maybe over 100 papers published based on made-up data. This comes just months after Harvard's Marc Hauser resigned over unspecified data-meddling activities.

What disturbs me is not just that this fraud happened, but the way it was detected. Both Stapel and Hauser were busted by their own junior lab members. Browsing Retraction Watch and reading over other fraud cases reveals that fraud is almost always detected either by 1) By readers of published papers who notice oddities in the data, or 2) by internal whistleblowers, almost always junior lab members

But these are both ad hoc methods. They rely heavily on individual vigilance and courage in speaking out (especially in the latter case). It seems to me that there's no working mechanism for catching fraud. If there were, such acts of individual heroism wouldn't be needed.

So whose job is it to catch fraud? At the moment, it's all the work of private investigators. Where are the police?

First off, is it the job of journals? That seems plausible. Journals publish scientific papers and by doing so they are saying, implicitly, that the papers are good quality. The way this works is meant to be through peer review.
But peer review is failing to catch many cases of fraud. I guess we don't know how many fraudlent papers are caught at the peer review stage and never published. But one would hope that such cases would come to light anyway because reviewers who suspect fraud ought to alert the relevant authorities. I can't think of any recent cases in which fraud investigations were started by peer reviewers, or at least not that we know about.

Maybe it's up to the institution that employs the fraudster? It's the institution that carries out investigations, "convicts" the fraudster and enacts the punishment. Clearly it's in their interests to do this because they don't want to be seen as soft on misconduct. But rarely do they go out and proactively try and catch or prevent fraud. It's not in their interests to do that.

Undetected fraud does no harm to anyone's reputation. On the contrary fraudsters are often the "stars" of their faculty until they get caught. Hauser and Stapel were. Plus, a department that got a reputation for hard-hitting anti-fraud measures might struggle to recruit people, even perfectly innocent ones who just found it annoying.

So what we see is departments who perform (fairly) good investigations into fraud, but only when someone else tells them to.

Maybe it's the funding bodies? They're paying for the research, so they clearly have an interest in making sure their money is well spent. At present, though, they lack the mechanisms to investigate it.

So those are the three possibilites as I see them - journals, institutions and grant awarders. While all of these organizations have policies for investigating and punishing fraud when it comes to light, they rarely (if ever) actually catch it, leaving this hazardous and stressful job to individuals.

Is there a better way?