Neuroskeptic Irreverent and Sometimes Profane, Study Finds

I was most surprised and honored to find out this morning that the Annals of Neurology has declared Neuroskeptic to be

Irreverent, sometimes profane, and can skirt the boundaries of good taste. Nonetheless, Neuroskeptic covers a rich mixture of important, engaging, or amusing topics focusing on the basic and clinical neurosciences, and does so in a data-driven, user-friendly, and comment-enabled format. Neuroskeptic is only one of a number of increasingly used web sites and blogs dedicated to promoting public education, rational discourse, and a healthy dose of skepticism around important issues in the neurosciences...

No really: Scientific literacy and the media. They also list a small number of other neuroblogs, although they leave out many outstanding ones including the blog that most inspired this one, and that everyone confuses me with, The Neurocritic.

Anyway, the editorial goes on to note that:

Last April, a series of sensationalist stories reporting the “creation of life” and a newfound capability to “play God” appeared in the national media following the demonstration that synthetic DNA could transform a mycoplasma species from one to another subtype(ref). This represented a tour de force of DNA synthesis, but probably only a modest step forward for the science of genetic engineering.

In response, President Obama directed his Presidential Commission for the Study of Bioethical Issues to prepare a comprehensive advisory report to help frame policies about synthetic biology(ref).

The Commission noted that sensationalist headlines may attract readers to scientific topics but do a terrible disservice by promoting “claims that fail to convey accurately to the public the current state of the field, the implications of research results, and the limits of scientists' present knowledge and abilities.” The Presidential Commission recommended creating a well-funded, interactive website... to monitor claims about new scientific discoveries and technologies.

Ideally, such a site would be only part of a wider effort to promote scientific literacy and critical thinking across all segments of society... In the coming years, scientific innovation is certain to play an increasingly large role in the global economy... The public discourse on these and related matters needs to be rational, evidence-based, and accurate.

Broadly speaking, this is why I write this blog, because it is indeed extremely important. Well, ok, the real reason is that it gives me an excuse to make funny pictures with MS Paint (someone accused me of using Photoshop to do those once - no, that would be too advanced). However, if a few people understand neuroscience a bit better in the process, I can live with that...

Hauser, S., & Johnston, S. (2011). Scientific literacy and the media Annals of Neurology, 69 (3) DOI: 10.1002/ana.22410

British Government Fails Maths, Economics

The British government has decided to change the way English universities are funded. They say that this will improve teaching quality; I doubt it. Worse, however, is that the new scheme, the stated justification for which was to save money, is now seriously at risk of being too expensive. From next year universities will be allowed to charge up to £9,000 per year for undergraduate courses, up from the current limit of just over £3,000. However the government is also cutting their basic funding allowance by 80% to compensate. So government pays less and students pay more - eventually; the government will pay all the money up front in the form of a loan to the students.

The government's cost projections assumed that the mean fee at English universities, and hence the mean size of their loans, would be £7,500 per year. Why, no-one seems to know. Sources are unanimous that this was what they assumed, but no-one links to any kind of report explaining why. Maybe they gazed into a magic crystal ball. Parliament, performing a separate analysis, also worked under the assumption of £7,500, and their reason was that

we have assumed that... this fee covers the 80% reduction in [central government funding]. The average fee... is assumed to be £7,500 per annum for an undergraduate degree.

However, this is just silly. For averagefees to be £7,500, anyone charging some amount more than that, would have to be balanced out by someone charging the same amount less. That's what an average is.

However, no-one can afford to charge less, even if they wanted to, because they need to charge £7,500 to pay for their teaching and break even. £7,500 is the minimum not the average. But plenty will want to charge more. Oxford and Cambridge, for instance, were blatantly going to charge the top amount, because they're "top" universities. As a result, every other university which aspires to be elite will have to charge £9k, to keep up with Oxbridge.

Hence a domino effect goes down the line: every university will want to charge as much as the ones immediately ahead of them, so as not to look cheap. (The alternative, that they'd try to undercut them in price, makes no sense when you consider the amounts of money involved; the savings to the students would be minimal but the message - "we are cheap, therefore not very good" - would be loud and clear.)

I've whipped up a little plot showing all the universities which have currently announced their fees along with their position in the latest university rankings. A few small institutions are unranked and so don't appear.

The rankings go up to 115 so if the universities ranked over 58 charge over £7.5k, the others would have to charge less to cancel them out. I'll try to update this chart when fees are announced, but I think it's a forgone conclusion that this won't happen. Last updated 06/04/2011 10 am. See also here for a frequently-updated expert analysis.

The government is now seriously talking about having to cut what little direct university funding remains, in order to avoid losing money - from a policy which was supposed to save money. Yet this was always going to happen given what I said above. Indeed this policy, which was sold to the country as a cost-cutting measure, was always going to, at best, break even until the graduates repay their loans, and they won't even start doing that until the first batch graduate, in 2015 which is the next election year.

So there seem to be only two possible options. Maybe they knew it wouldn't save money, but in that case, why did they do it? It's not winning them any votes, so there must be a long-term plan, but what? The other possibility is that they genuinely thought it would save money. So it's a question of bungling incompetence vs. mysterious scheme. I'm not sure which is worse.

Fake Clinical Trial - Real Problems

Here at Neuroskeptic we've seen our fair share of dubious clinical trials over the years, but the Indian Journal of Psychiatry has just published one which really takes the biscuit, because it was completely made up.



Luckily, the trial is actually a rather neat spoof paper, written for educational purposes to highlight bad practices in the design and writing up of clinical trials. It's accompanied by a serious piece which analyzes these problems. They're both open access so you can take a look.

The sham study is ostensibly a trial of a new antidepressant, "placeboxetine", compared to an older drug for depression - but it was really written by one of the Editors of the journal via "Common shortcomings in manuscripts submitted to the Indian Journal of Psychiatry were collated into a single manuscript". These shortcomings are certainly not limited to Indian papers.

The problems included:

• No placebo group. This is extremely common in trials comparing two drugs, so it's "accepted practice", but it's still a bad thing.
  
• The "placeboxetine" was given at a higher dose, relative to its dose range, than the comparison drug but they don't say why.
• Side effects are reported but they don't explain how these were assessed. If you specifically ask about them you find a lot more than if you rely on patients to spontaneously complain.
• Subtle, but important, issues with the statistics, such as reliance on t-tests over more appropriate methods.
• The trial had some unusual features for a depression trial - with no explanation. Most patients were males in their 20s, while the norm is for about 65% females and an average age in the 40s; very few people dropped out; very few people who were screened were excluded, whereas most trials exclude loads of people for all kinds of reasons.
• The effectiveness of both drugs was remarkably high (75% cure rate over 6 weeks - better than any treatment, drug or therapy, would be expected to show.) Yet they don't mention this.
• It was badly written. The title in particular was far too long and clumsy.
• It turns out that the trial was sponsored by the fictional pharmaceutical company, and was probably conducted to help get placeboxetine sold in India - but we only find this out in the small print at the end.
• Hot pink and white is not a good color scheme for your graphs, or for anything except marshmallows. (I may have added this myself.)
  

Overall I think this kind of thing is extremely valuable. The author's final comments, however, are a bit questionable. He advises people running clinical trials to base their research protocol, and their paper, on previously published studies of a similar nature published in good journals. Unfortunately, even leading journals publish stuff which suffers from some of these problems...

Andrade C (2011). A 6-week, multicentre, randomized controlled clinical trial to evaluate the safety and efficacy of placeboxetine hydrochloride in the treatment of major depressive disorder in an Indian setting. Indian journal of psychiatry, 53 (1), 69-72 PMID: 21431013

Andrade C (2011). Placeboxetine for major depressive disorder: Researcher, author, reader, and reviewer perspectives on randomized controlled trials. Indian journal of psychiatry, 53 (1), 73-6 PMID: 21431014

A Stroke Of Good Fortune Cures OCD?

A 45 year old female teacher had a history of severe obsessive-compulsive disorder, along with other problems including ADHD. Her daughter, and many other people in her family, had suffered the same problems and in a few cases had Tourette's Syndrome.But all that changed - when she suffered a stroke. This is according to a brief case report from Drs. Diamond and Ondo of Texas:

[she] had a long history of constant intrusive and obsessive thoughts that interrupted her daily activities and sleep. She had constant unfounded fears that something bad would happen to her family and had persistent violent thoughts of using knives to harm family members. She would check the door locks up to 15 times a day. In addition to her OCD symptoms, she had ... inattention, poor concentration, and difficulty sitting still.

She had never been treated for the OCD, despite how it interfered with her life, because she feared losing her job as a teacher if she sought psychiatric help. But then...

Nine months before approaching us, she developed the acute onset of paresthesia [weird sensations] and weakness in the left upper extremity and face, associated with slurred speech. Initially, she was unable to lift her arm against gravity.

These are classic signs of a stroke, but it was a very mild one, because the symptoms only lasted a few minutes and were pretty much gone even before she arrived at the emergency room. She made a full recovery. More than a full recovery in fact:

Within weeks of her stroke, she realized that her obsessive and intrusive thoughts, fears, rituals, and impulsive behavior had completely resolved. In addition, there was some improvement in her temperament. There was no improvement in attention or concentration. Owing to her improvement in neuropsychiatric symptoms, she strongly felt that her stroke was beneficial. These benefits have persisted for 24 months.

Most medical case reports concern patients who died, or got really sick, in a particularly interesting fashion, but this one has a happy ending. Strokes can be devastating, of course, although people also make full recoveries - it all depends on the severity of the stroke, and whether they get prompt treatment.

There have been a few other cases of brain damage which brought unexpectedly beneficial effects. In Vietnam veterans, for example, people with damage to the vmPFC due to combat trauma seemed to be protected from depression.

Whether the stroke really cured her, or whether it was some kind of psychological "placebo" effect, we'll never know. It's hard to see why a stroke would have a placebo effect, but on the other hand, an MRI scan revealed that the stroke occured in an area of the brain - the right frontoparietal cortex - which is fairly low down on the list of "OCD-ish" areas.

The authors make some vague comments about "modulation of the cortical–subcortical circuits" but this is really the neuroscientific equivalent of saying "We guess it did something", because the entire brain is made of cortical-subcortical circuits, given that the cortex is at the top and everything else is, by definition, the sub-cortex. It's quite possible. But we really can't tell.

Diamond A, & Ondo WG (2011). Resolution of Severe Obsessive-Compulsive Disorder After a Small Unilateral Nondominant Frontoparietal Infarct. The International journal of neuroscience PMID: 21426244

British Education - Malaysian Money

The University of Wales (not in fact the only university in Wales) is a troubled place.


Last year, a BBC Wales piece provided damning evidence about three of their approved overseas courses: a Thai fashion school unaccredited in Thailand; a Malaysian business school run by a pop-star with bogus degrees, and an American Bible college which, as well as teaching fundamentalist ideas, is unaccredited - well, except by the University of Wales.

These kinds of courses are accredited to award University of Wales undergraduate and even graduate degrees. You study there - you get a degree from Wales. They've since cut ties with the offending institutions but another one, in Singapore this time, is now in the spotlight. The investigation is ongoing but here's what some Singaporeans think of the questionable college.

If this had happened once, it might be written off as an exceptional event, but given that it's happened three or four times, it's an institutional failure. Why would a university risk ruining its own reputation by associating with dodgy degree-mills? Well, the thing is - and the university admits this - these courses are a key source of funding:

"The university said the profits from its international validation programmes were invested in Welsh higher education."

So we have a conflict of interest. From a business perspective it doesn't matter if the "accredited partner" is teaching that the earth is flat, so long as they pay up.

That's bad but it gets worse. We have a British university, which is reliant on funding from overseas colleges. These colleges of course have to make a profit themselves, and they make money from their students. So the UoW is taking money from foreign students - many of them frm countries considerably poorer than Britain - to fund the British education system. Is this ethical? Are these students getting their money's worth?

Clearly every case is unique and most of the accredited courses are probably fine, but the problem is, it's hard to know. When three or four dodgy courses have managed to slip through the net, you have to ask whether the net of "quality assurance" is working

The BBC Wales program contained a reminder of the kind of issues at play here. "Dr" Fazley Yakoob "MBA", the Malaysian pop-star, at one point said that people were keen to get University of Wales degrees via his college because of the glamour attached to the fact that the Prince of Wales is Chancellor of that institution.

Now this will have had most British people laughing into their tea because over here, Charles, Prince of Wales is regarded as out-of-touch, arrogant, and a bit of a crackpot. He's best known for his views on alternative medicine, for talking to plants, and his dislike for modern architecture. Certainly he has little of the respect accorded to the Queen, or to his sons Harry (fought in Afghanistan) or William (handsome, getting married).

Yet the British monarchy is, for some reason, probably more popular outside of the UK than inside it; perhaps some people elsewhere think that the fact that the UoW is associated with Prince Charles means that their accredited courses must be legitimate.

The University of Wales seems to be reaching the end of its lifespan, with a new report saying it should probably close soon. But the industry of overseas accreditation by British universities seems unlikely to go away.

As British universities lose public funding they're being forced to seek money from elsewhere. British students of course will be first in line, which I'm not happy with but they will at least be paying a fair price for their education; universities will be limited by law to charging £9000 per year which is basically the cost price for a year's teaching (plus a thousand or so on top - but with inflation, not for long). The idea that British students could be subsidized by Malaysians, however, is very worrying.

Turn That Off, I'm Writing

I listen to a lot of music.

Music is playing in the background most of the time whether I'm on the computer or not (thanks to my old, poorly-designed but still faithful Shuffle). However I've noticed that I find myself turning off iTunes when I'm writing.

Right now, for example, I have just put this song on pause because I'm writing this post (a post about why I paused that song - bit of a chicken-and-egg situation there.) I can't write with a song on, because the lyrics would be distracting.

However, I don't always do this when I'm typing. With some songs, and some kinds of writing, it's OK. I think this is how it works:

Instrumental songs are obviously OK. But I don't listen to many.

More interestingly, songs I've listened to many times are fine. I've just put on this which, according to iTunes, I have listened to no fewer than 140 times over the last three years. And this is fine. No distraction. I think the reason must be that I'm so used to the lyrics that the language part of my mind no longer needs to work out what they mean.

Some kinds of writing are compatible with songs. Blogging isn't and writing "important" emails aren't but a lot of emails are. Which I guess means that I'm not really putting much effort into writing them. I must be typing on auto-pilot, just repeating stock phrases ("Sounds good") rather than actually using my language areas, or at least, not using them very hard.

Psychologists are fond of using these kinds of selective distraction tasks to map out the architecture of the mind e.g. verbal ones distract verbal working memory but not spatial, and vice versa. So this is all pretty standard stuff, but what's interesting is that it's not intuitively obvious.

It doesn't feel like sometimes when I'm writing my language faculty is hard at work, and other times it's not. It feels like I'm thinking about what I type all the time. It's just typing. Sometimes I'll be replying to a bunch of emails, music on full blast, and then I'll find myself putting it on pause when I get to one particular email; but I couldn't tell you in advance which one it would be. It just feels right. Better turn the music off for this one, this one's serious - though even that's putting it too strongly. It doesn't feel serious, it just feels like the music needs to be off.

Our concious experience is smooth and seamless even though we're constantly switching between using different parts of our brains. This becomes all too evident in the case of brain lesions, which can rob us of capacities we never knew we had, because they were always there when we needed them. Some lesions, for example, render you completely unaware of anything that happens to your left. It doesn't seem like we're using a different part of our brain when dealing with stuff on the left as opposed to the right - but we are.

Depressed or Bereaved? (Part 2)

In Part 1, I discussed a paper by Jerome Wakefield examining the issue of where to draw the line between normal grief and clinical depression.


The line moved in the American Psychiatric Association's DSM diagnostic system when the previous DSM-III edition was replaced by the current DSM-IV. Specifically, the "bereavement exclusion" was made narrower.

The bereavement exclusion says that you shouldn't diagnose depression in someone whose "depressive" symptoms are a result of grief - unless they're particularly severe or prolonged when you should. DSM-IV lowered the bar for "severe" and "prolonged", thus making grief more likely to be classed as depression. Wakefield argued that the change made things worse.

But DSM-V is on its way soon. The draft was put up online in 2010, and it turns out that depression is to have no bereavement exclusion at all. Grief can be diagnosed as depression in exactly the same way as depressive symptoms which come out of the blue.

The draft itself offered just one sentence by way of justification for this. However, big cheese psychiatrist Kenneth S. Kendler recently posted a brief note defending the decision. Wakefield has just published a rather longer paper in response.

Wakefield starts off with a bit of scholarly kung-fu. Kendler says that the precursors to the modern DSM, the 1972 Feighner and 1975 RDC criteria, didn't have a bereavement clause for depression either. But they did - albeit not in the criteria themselves, but in the accompanying how-to manuals; the criteria themselves weren't meant to be self-contained, unlike the DSM. Ouch! And so on.

Kendler's sole substantive argument against the exclusion is that it is "not logically defensible" to exclude depression induced by bereavement, if we don't have a similar provision for depression following other severe loss or traumatic events, like becoming unemployed or being diagnosed with cancer.

Wakefield responds that, yes, he has long made exactly that point, and that in his view we should take the context into account, rather than just looking at the symptoms, in grief and many other cases. However, as he points out, it is better to do this for one class of events (bereavement), than for none at all. He quotes Emerson's famous warning that "A foolish consistency is the hobgoblin of little minds". It's better to be partly right, than consistently wrong.

Personally, I'm sympathetic to Wakefield's argument that the bereavement exclusion should be extended to cover non-bereavement events, but I'm also concerned that this could lead to underdiagnosis if it relied too much on self-report.

The problem is that depression usually feels like it's been caused by something that's happened, but this doesn't mean it was; one of the most insidious features of depression is that it makes things seem much worse than they actually are, so it seems like the depression is an appropriate reaction to real difficulties, when to anyone else, or to yourself looking back on it after recovery, it was completely out of proportion. So it's a tricky one.

Anyway, back to bereavement; Kendler curiously ends up by agreeing that there ought to be a bereavement clause - in practice. He says that just because someone meets criteria for depression does not mean we have to treat them:

...diagnosis in psychiatry as in the rest of medicine provides the possibility but by no means the requirement that treatment be initiated ... a good psychiatrist, on seeing an individual with major depression after bereavement, would start with a diagnostic evaluation.

If the criteria for major depression are met, then he or she would then have the opportunity to assess whether a conservative watch and wait approach is indicated or whether, because of suicidal ideation, major role impairment or a substantial clinical worsening the benefits of treatment outweigh the limitations.

The final sentence is lifted almost word for word from the current bereavement clause, so this seems to be an admission that the exclusion is, after all, valid, as part of the clinical decision-making process, rather than the diagnostic system.

OK, but as Wakefield points out, why misdiagnose people if you can help it? It seems to be tempting fate. Kendler says that a "good psychiatrist" wouldn't treat normal, uncomplicated bereavement as depression. But what about the bad ones? Why on earth would you deliberately make your system such that good psychiatrists would ignore it?

More importantly, scrapping the bereavement criterion would render the whole concept of Major Depression meaningless. Almost everyone suffers grief at some point in their lives. Already, 40% of people meet criteria for depression by age 32, and that's with a bereavement exclusion.

Scrap it and, I don't know, 80% will meet criteria by that age - so the criteria will be useless as a guide to identifying the people who actually have depression as opposed to the ones who have just suffered grief. We're already not far off that point, but this would really take the biscuit.

Wakefield JC (2011) Should Uncomplicated Bereavement-Related Depression Be Reclassified as a Disorder in the DSM-5? The Journal of nervous and mental disease, 199 (3), 203-8 PMID: 21346493

A Look Inside A Brain

A remarkable paper just out in Nature has revealed images of the brain's structure and function in unprecedented detail: Network anatomy and in vivo physiology of visual cortical neurons.

Harvard Medical School researchers Bock et al took a mouse - just one - and used two forms of microscopy to investigate a small patch of it's primary visual cortex, the area which receives input from the eyes.

First, they used two-photon calcium imaging to look at the functional properties of individual cells. They displayed various kinds of patterns in front of the mouse's eyes, and looked to see which cells lit up, using a special dye which become fluorescent in the presence of calcium, which rises inside cells when they fire.

Having done that they took the same chunk of cortex (a rough cube of about 0.4 mm on each side) and used electron microscopy to see it in its entirety. This was the tricky part. Electron microscopy only works if the sample is first cut into extremely thin slices. Each of the 1,200 slices took 20 minutes to image so in total they spent "several months" to get it all done, using a home-made device consisting of 4 high-resolution digital cameras that fed the information to an image processing system.

In total, they acquired 36 terabytes of electron microscope images, and after processing it all they ended up with a 3D picture of 10 million megapixels. My phone has a 16 GB internal storage and a 5 megapixel camera, so in order to get this data I would have to take 2 million photos, and it would take over 2000 phones to store them. There isn't an app for that...yet.

The end result was some very pretty pictures, and amazing movies. Oh, and also, some science - they were able to compare the functional properties of brain cells to their actual physical wiring diagram. This, in the broadest sense, is what all neuroscientists are trying to do; Bock et al, however, went out and did it directly.

They were able to test an important hypothesis, namely that in the visual cortex, pyramidal cells (the main cortical cell type) project to inhibitory GABA interneurons in a manner which doesn't depend on their orientation-selectivity - whether they respond most strongly to seeing vertical lines, horizontal lines, diagonal ones, etc. Bock et al found that this seemed to be true: pyramidal cells synapsed onto whichever GABA cells happened to be nearest to them, regardless of their orientation-selectivity.

Still, it took them several months to image an area containing just 1,000 neurons. The mouse cortex has 4 million, and the human cortex has 11,000 million, so this is a tiny fraction of the whole brain, and the small size of the area meant that they were only able to examine short-range connections between neighbouring cells, not long-range wiring. So this is early days, but it's clearly an extremely exciting technique and is sure to open the way to major advances in the future.

Link: Also blogged at Brains Lab.

Bock DD, Lee WC, Kerlin AM, Andermann ML, Hood G, Wetzel AW, Yurgenson S, Soucy ER, Kim HS, & Reid RC (2011). Network anatomy and in vivo physiology of visual cortical neurons. Nature, 471 (7337), 177-82 PMID: 21390124

Black Bile and Black Dogs

Depression is black. That's been the view of Western culture ever since the ancient Greeks, with their concept of "melan cholia" (μελαγχολία) - black bile. The idea was that psychological states were associated with particular bodily fluids; melancholy was associated with the "black bile" of the spleen, as opposed to the go-getting, passionate "yellow bile" of the gall-bladder

What this "black bile" (melan chole) actually was is rather mysterious. The gall bladder does indeed produce bile, a digestive juice which is greenish-yellow, but the spleen doesn't secrete anything as such. It itself is a dark greyish-purple, which might have given rise to the idea that it contained something black. Here's another theory.

The other color associated with depression is blue, of course, as in The Blues. However, when picturing depression-blue, I think most people generally see it as something rather close to black. It's the sky at twilight, not a bright summer's day, right? It's not a happy blue.

Winston Churchill famously referred to his depression as his Black Dog. There's a rather nice correspondence here with Chinese, though I doubt Churchill knew it. Here's the Chinese character for black and (one of) the characters for dog:
Write these as two separate characters and it says, well, black dog (badly). But there's another character which consists of "black" & " dog" combined:

This means silence; quiet; speechless; mute.

This is as good a one-word description of depression as any. Churchill's metaphor has always struck me as slightly misleading in one sense (although it's excellent in others): depression is not a thing; not even a black one. It is a lack, of motivation, energy, joy, imagination; you don't wake up and feel depressed, you wake up depressed and feel terrible, but the depression is hidden, only evident in retrospect, just as you don't tend to notice how quiet it is until a noise breaks the silence.

Neural Correlates of 80s Hip Hop

A ground-breaking new study reveals the neurological basis of seminal East Coast hip-hop pioneers Run-D.M.C.

The study is Diffusion tensor imaging of the hippocampus and verbal memory performance: The RUN DMC Study, and it actually has nothing to do with hip-hop, but it does have one of the best study acronyms I have ever seen.

RUN DMC stands for the "Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort study".

Or maybe it does relate to rapping. Because the paper is about verbal memory, and if there's one thing a rapper needs, it's a good memory for words, otherwise they'd forget their lyrics and... OK no, it doesn't relate to hip-hop.

It is however a very nice piece of research. They took no fewer than 503 elderly people - making this by far the single biggest neuroimaging study I have ever read. They used DTI to measure the quality of white-matter tracts in the brain and correlated this with verbal memory function. DTI is an extremely clever technique which allows you to measure the integrity of white matter pathways.

The theory behind the study is that in elderly people, white matter often shows degeneration. This is thought to be caused by vascular disease - problems with the blood flow to the brain, such as cerebral small-vessel disease which means, essentially, a series of mild strokes, which often go unnoticed at the time, but they build up to cause brain damage, specifically white matter disruption.

The symptoms of this are extremely varied and can range from cognitive and memory impairment, to depression, to motor problems (clumsiness), all depending on where in the brain it happens.

All of the people in this study had cerebral small-vessel disease as defined on the basis of symptoms and the presence of visible white matter lesions on the basic MRI scan. The authors found that the integrity of the white matter tracts in the area of the hippocampus, as measured with DTI, correlated with performance on a simple word learning task:


The healthier the hippocampal white matter, the better people did on the task. This makes sense as the hippocampus is a well known memory centre. This is only a correlation, and doesn't prove that the hippocampal damage caused the memory problems, but it seems entirely plausible. The authors controlled for things like age, gender, and the size of the hippocampus, as far as possible.

Should we all be worried about our white matter when we get older? Quite possibly - but luckily, the risk factors for vascular disease are quite well understood, and many of them are things you can change by having a healthy lifestyle.

Smoking is bad news, as are hypertension (high blood pressure), obesity, and high cholesterol. Diabetes is also a risk factor. So you should quit smoking, eat well, and ensure that you're getting tested and if necessary treated for hypertension and diabetes. All of which, of course, is a good idea from the point of view of general health as well.




van Norden AG, de Laat KF, Fick I, van Uden IW, van Oudheusden LJ, Gons RA, Norris DG, Zwiers MP, Kessels RP, & de Leeuw FE (2011). Diffusion tensor imaging of the hippocampus and verbal memory performance: The RUN DMC Study. Human brain mapping PMID: 21391278

Science/Journalism

I was at a discussion the other day about science and the media. Some scientists and some journalists were there. As a scientist, talking to other researchers was a bit of an echo chamber - everyone had very similar comments, mostly negative, about the media coverage of science.

But hearing from journalists was interesting and I've put together this handy guide to the differences between science and journalism as professions:


There seem to be three main sticking points. Note that this is mainly relevant to news journalism - "Scientists today announced..."; feature writing largely avoids these issues. I think it also applies to the British media somewhat more than elsewhere.

Time: Compared to science, journalists work at a supersonic speed. Whereas a scientific journal can claim "rapid publication" if it only takes two months from submission to print, a news journalist is expected to write up a story in hours. News must be new, and if one of their rivals scoops them, they lose the story. So even with the best will in the world, journalists are never going to be able to give stories what, to a scientist, would be "sufficient consideration" i.e. a couple of days thought at least.

Expertise: The average scientist knows an awful lot about their sub-sub-speciality of a particular branch of science. By contrast most 'science journalists' are just that - they cover science, all of it. A few are lucky enough to have a "speciality", like environmental issues or physics, but this is is still vast by scientific standards. They're not stupid, and with a few days of study, I'm sure it would be possible for them to grasp the science behind every story they cover. However, they just don't have that time.

Goal: For a scientist, an interesting article is one which adds to their own understanding. Given that modern scientists are world experts in a very narrow field (see above), this means they are mostly interested in stuff which only they and maybe 20 or 30 other people will appreciate. To a journalist writing for an audience of millions, that's by definition irrelevant. If this means they have to draw tenuous conclusions between the science and the hot topics that sell stories - cancer, children, cute animals, and controversies - they'll just have to do that.

In summary, journalists and scientists have completely different agendas. So "good science journalism", in the sense of stuff that scientists and journalists will be equally happy with, is a contradiction in terms. Except maybe in the rare cases of sudden breakthroughs that genuinely involve hot topics, like say the discovery of a cute new species. This is not the fault of individual journalists; it's a structural problem.

*

So my feeling is that reporting science as news is inherently flawed from a scientific perspective. The core of the problem is time. Even a world-expert scientist would struggle to make a serious evaluation of some new science in a few hours. A journalist who has to write about everything from swine flu to the Large Hadron Collider, all in the same day, has no chance. This is not the fault of individual journalists; it's a structural problem.

But the problem is not limited to science journalism. Newspaper journalism is in crisis as we all know. Sales and profits are falling so jobs are cut and the few remaining people have to shoulder the same workload. Cheap junior reporters and unpaid interns increasingly replace expensive veterans. Under enormous time pressures, journalists have no choice but to rely heavily on press releases. This can't go for ever - something has to give.

So what's the solution? This is going to make me sound like a right arse but I think the answer is... blogging. Not as a replacement for science journalism, but as an complement to it. A science blogger can act as an intermediary between raw science and journalists.

Bloggers generally write about what they know, bringing specialist expertise. Each individual blog has a fairly narrow specialist focus, but the other side of that coin is that they dig deeper than journalists can. Maybe it takes them a couple of days - but the stories they uncover are ones that inherently can't be generated any quicker. Here's a great example. Science blogs are a kind of second source of news stories on top of the primary literature.

And they do this for free, which is lucky because no-one would pay us for it. Journalists obviously can't just copy and paste from blogs, but I think almost any blogger would be only too glad for their work to be borrowed for a mainstream media piece so long as it contained a link back to the original (bloggers love to hate the mainstream media but nothing makes us happier than getting mainstream media coverage, seriously).

Depressed Or Bereaved? (Part 1)

Part 2 is now out here.

My cat died on Tuesday. She may have been a manipulative psychopath, but she was a likeable one. She was 18.On that note, here's a paper about bereavement.

It's been recognized since forever that clinical depression is similar, in many ways, to the experience of grief. Freud wrote about it in 1917, and it was an ancient idea even then. So psychiatrists have long thought that symptoms, which would indicate depression in someone who wasn't bereaved, can be quite normal and healthy as a response to the loss of a loved one. You can't go around diagnosing depression purely on the basis of the symptoms, out of context.

On the other hand, sometimes grief does become pathological - it triggers depression. So equally, you can't just decide to never diagnose depression in the bereaved. How do you tell the difference between "normal" and "complicated" grief, though? This is where opinions differ.

Jerome Wakefield (of Loss of Sadness fame) and colleagues compared two methods. They looked at the NCS survey of the American population, and took everyone who'd suffered a possible depressive episode following bereavement. There were 156 of these.

They then divided these cases into "complicated" grief (depression) vs "uncomplicated" grief, first using the older DSM-III-R criteria, and then with the current DSM-IV ones. Both have a bereavement exclusion for the depression criteria - don't diagnose depression if it's bereavement - but they also have criteria for complicated grief which is depression, exclusions to the exclusion.

The systems differ in two major ways: the older criteria were ambiguous but at the time, they were generally interpreted to mean that you needed to have two features out of a possible five; prolonged duration was one of the list and anything over 12 months was considered "prolonged". In DSM-IV, however, you only need one criterion, and anything over 2 months is prolonged.

What happened? DSM-IV classified many more cases as complicated than the older criteria - 80% vs 45%. That's no surprise there because the criteria are obviously a lot broader. But which was better? In order to evaluate them, they compared the "complicated" vs "normal" episodes on six hallmarks of clinical depression - melancholic features, seeking medical treatment, etc.

They found that "complicated" cases were more severe under both criteria but the difference was much more clear cut using DSM-III-R.

Wakefield et al are not saying that the DSM-III-R criteria were perfect. However, it was better at identifying the severe cases than the DSM-IV, which is worrying because DSM-IV was meant to be an improvement on the old system.

Hang on though. DSM-V is coming soon. Are they planning to put things back to how they were, or invent an even better system? No. They're planning to, er, get rid of the bereavement criteria altogether and treat bereavement just like non-bereavement. Seriously. In other words they are planning to diagnose depression purely on the basis of the symptoms, out of context.

Which is so crazy that Wakefield has written another paper all about it (he's been busy recently), which I'm going to cover in an upcoming post. So stay tuned.

Wakefield JC, Schmitz MF, & Baer JC (2011). Did narrowing the major depression bereavement exclusion from DSM-III-R to DSM-IV increase validity? The Journal of nervous and mental disease, 199 (2), 66-73 PMID: 21278534

How Not To Improve University Teaching

The British government has recently changed the rules on university funding. At present, students pay no more than £3,000 per year for their tuition, with the rest of the roughly-£7500 it costs to teach one student being paid for by the state.

From next year, students will pay up to £9000 per year and the state will hardly pay anything. This was sold to the nation as a way to cut the budget deficit after the Recent Financial Unpleasantness, although it won't achieve this for several years, if at all, because the government will loan students the money upfront and they'll then gradually pay it back after they graduate.

However, another supposed benefit of the changes is that they'll give universities an incentive to improve their teaching. Students, we're told, will demand high quality teaching, now that they are the ones paying for it, and institutions which fail to provide this will lose out as students choose somewhere else.

Which is a cute little idea, and there may be a few people out there who actually believe it, but there's one problem: universities don't teach anyone, academics do. And academics have no incentive to teach well and, in most cases, no incentive to make sure that their university has a reputation for good teaching.

As an academic your career is research. The way you get a job, and a promotion, and grants and money and influence, is by publishing papers. You don't get ahead by teaching well. Academics teach because it's written into their university contract that they have to do a certain amount of teaching. Or in the case of junior academics who don't have a lectureship yet, they teach because their salaries are low relative to the cost of getting the qualifications required (BSc + MSc + PhD = £££) and they need the money.

This doesn't mean that all academics resent teaching, although sadly many do. Some are fine with it, and some enjoy it. Some, generally the latter ones, are extremely good at it. But even they have no incentive to be good at it or to improve their teaching. If it comes down to a choice between spending a week preparing a set of awesome lectures, or a week in the lab, the incentive is, by the nature of academic careers, always going to be towards research.

OK, but don't researchers benefit from working at a prestigious university? Doesn't that look good on your CV? Yes (although not as good as publications) but this doesn't mean they have an incentive to make their university more prestigious - because in most cases it's only "their" university for a few years at maximum.

Until you get to the level of tenured professor, if ever, you cannot assume that you'll be working in the same place for very long. Many academics will go to one university for their undergraduate degrees, another for their masters, another for their doctorate, and then another two or three as junior faculty member before they "settle down" - and the majority don't make it that far. And these are not uncommonly on different continents. Tenured professors are the only ones with a material interest in the future of their institution and they usually delegate their teaching anyway.

So what will the new fees changes achieve? They'll give university managers an incentive to try to improve teaching but managers don't teach. So they'll try to get their academics to teach better - but it is very unclear that this is possible.

I think we'll be seeing more "training courses", "teaching support officers" and other managerial initiatives, along with ever-glossier marketing brochures, but whether this will achieve anything is doubtful. The essence of good teaching isn't training, it's motivation - you have to want to teach well. You have to be passionate about your subject, you have to care about your students, and you have to put in the hours.

So long as teaching doesn't contribute to academic career prospects, many will see it as a burden and these training courses as yet another distraction from their research - and from their teaching too, in fact. Change the nature of academia so that publications aren't everything and teaching is valued - then you'd improve teaching, and quite possibly research as well.

Paxil: The Whole Truth?

Paroxetine, aka Paxil aka Seroxat, is an SSRI antidepressant.

Like other SSRIs, its reputation has see-sawed over time. Hailed as miracle drugs in the 1990s and promoted for everything from depression to "separation anxiety" in dogs, they fell from grace over the past decade.

First, concerns emerged over withdrawal symptoms and suicidality especially in young people. Then more recently their antidepressant efficacy came into serious question. Paroxetine has arguably the worst image of all SSRIs, although whether it's much different to the rest is unclear.

Now a new paper claims to provide a definitive assessment of the safety and efficacy of paroxetine in adults (age 18+). The lead authors are from GlaxoSmithKline, who invented paroxetine. So it's no surprise that the text paints GSK and their product in a favourable light, but the data warrant a close look and the results are rather interesting - and complicated.

They took all of the placebo-controlled trials on paroxetine for any psychiatric disorder - because it wasn't just trialled in depression, but also in PTSD, anxiety, and more. They excluded studies with fewer than 30 people; this makes sense though it's somewhat arbitrary, why not 40 or 20? Anyway, they ended up with 61 trials.

First they looked at suicide. In a nutshell paroxetine increased suicidal "behaviour or ideation" in younger patients (age 25 or below) relative to placebo, whether or not they were being treated for depression. In older patients, it only increased suicidality in the depression trials, and the effect was smaller. I've put a red dot where paroxetine was worse than placebo; this doesn't mean the effect was "statistically significant", but the numbers are so small that this is fairly meaningless. Just look at the numbers.

This is not very new. It's been accepted for a while that broadly the same applies when you look at trials of other antidepressants. Whether this causes extra suicides in the real world is a big question.

When it comes to efficacy, however, we find some rather startling info that's not been presented together in one article before, to my knowledge. Here's a graph showing the effect of paroxetine over-and-above placebo in all the different disorders, expressed as a proportion of the improvement seen in the placebo group.

Now I should point out that I just made this measure up. It's not ideal. If the placebo response is very small, then a tiny drug effect will seem large by comparison, even if what this really means is that neither drug nor placebo do any good.

However the flip side of that coin is that it controls for the fact that rating scales for different disorders might be just more likely to show change than others. The d score is a more widely used standardized measure of effect size - though it has its own shortcomings - and I'd like to know those, but the data they provide don't allow us to easily calculate it. You could do it from the GSK database but it would take ages.

Anyway as you can see paroxetine was better, relative to placebo, against PTSD, PMDD, obsessive-compulsive disorder, and social anxiety, than it was against depression measured with the "gold-standard" HAMD scale! In fact the only thing it was worse against was Generalized Anxiety Disorder. Using the alternative MADRS depression scale, the antidepressant effect was bigger, but still small compared to OCD and social anxiety.

This is rather remarkable. Everyone calls paroxetine "an antidepressant", yet at least in one important sense it works better against OCD and social anxiety than it does against depression!

In fact, is paroxetine an antidepressant at all? It works better on MADRS and very poorly on the HAMD; is this because the HAMD is a better scale of depression, and the MADRS actually measures anxiety or OCD symptoms?

That's a lovely neat theory... but in fact the HAMD-17 has two questions about anxiety, scoring 0-4 points each, so you can score up to 8 (or 12 if you count "hypochondriasis", which is basically health anxiety, so you probably should), out of a total maximum of 52. The MADRS has one anxiety item with a max score of 6 on a total of 60. So the HAMD is more "anxious" than the MADRS.

This is more than just a curiosity. Paroxetine's antidepressant effect was tiny in those aged 25 or under on the HAMD - treatment just 9% of the placebo effect - but on the MADRS in the same age group, the benefit was 35%! So what is the HAMD measuring and why is it different to the MADRS?

Honestly, it's hard to tell because the Hamilton scale is so messy. It measures depression and the other distressing symptoms which commonly go along with it. The idea, I think, was that it was meant to be a scale of the patient's overall clinical severity - how seriously they were suffering - rather than a measure of depression per se.

Which is fine. Except that most modern trials carefully exclude anyone with "comorbid" symptoms like anxiety, and on the other hand, recruit people with symptoms quite different to the depressed inpatients that Dr Max Hamilton would have seen when he invented the scale in 1960.

Yet 50 years later the HAMD17, unmodified, is still the standard scale. It's been repeatedly shown to be multi-factorial (it doesn't measure one thing), no-one even agrees on how to interpret it, and a "new scale", the HAMD6, which consists of simply chucking out 11 questions and keeping the 6 that actually measure depression, has been shown to be better. Yet everyone still uses the HAMD17 because everyone else does.

Link: I recently covered a dodgy paper about paroxetine in adolescents with depression; it wasn't included in this analysis because this was about adults.

Carpenter DJ, Fong R, Kraus JE, Davies JT, Moore C, & Thase ME (2011). Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials. The Journal of clinical psychiatry PMID: 21367354

Earthquakes And Antipsychotics

According to a clever little paper just out from Italy, prescriptions for antipsychotic drugs skyrocketed in the months following a major earthquake. But there are some surprising details.


On 6th April 2009, an earthquake hit L'Aquila, a medium-sized city in central Italy. Out of about 100,000 people living in the L'Aquila area, over 600 died and over 60,000 were displaced: a major disaster for the local people.

Rossi et al from the University of L'Aquila looked at medication prescription in the 6 months following the earthquake and compared them to the previous 6 months. This is not an ideal method, it would have been better to compare L'Aquila to a neighboring district unaffected by the earthquake to control for nationwide changes; but over a few months we wouldn't expect large changes.

Anyway - they found that the number of "new" antidepressant prescriptions rose by 37%. However, prescriptions of non-psychiatric drugs like statins and anti-diabetic medications also rose by up to 50%. This is a bit sketchy but it suggests that the increase in antidepressants might just reflect increased post-disaster medical care for everyone in the area.

There was one big finding though: rates of antipsychotic prescribing more than doubled to 833 prescriptions, a 130% increase.

Does this mean that more people experienced psychosis in the aftermath of the trauma? That's one possibility - but a closer look reveals that the "extra" antipsychotics were given almost entirely to elderly people: just 0.3% of people under 45 got a new antipsychotic prescription but 1% of those 65-75 did and in those 75+ it reached 2.7% in men and a dizzying 3.8% of women.

Unfortunately Rossi et al couldn't tell what the drugs were being prescribed for, because their dataset was based on drug sales. However, it's known that schizophrenia and other forms of psychosis generally strike younger people, not the elderly. However, antipsychotics are often used as sedatives in elderly people especially those suffering dementia.

As the authors point out, this is a controversial practice:

A further observation concerns the appropriateness of prescribed drugs to a potentially vulnerable group such as the elderly. The majority of prescriptions were made by primary care physicians. This may partly explain the somewhat unusual increase in prescriptions for antipsychotic medications. It has been reported that antipsychotic medications are disproportionately prescribed to elderly subjects and need further regulation. This is particularly true in emergency and disaster situations.

In the UK a 2009 government report warned that antipsychotics were being used too freely in people with dementia, at the risk of causing significant harm, and said that they should be reserved for the most serious cases only. This study raises concerns that already questionable prescribing might get even worse following disasters.

Rossi A, Maggio R, Riccardi I, Allegrini F, & Stratta P (2011). A quantitative analysis of antidepressant and antipsychotic prescriptions following an earthquake in Italy. Journal of traumatic stress, 24 (1), 129-32 PMID: 21351173

Amy Bishop, Neuroscientist Turned Killer

Across at Wired, Amy Wallace has a long but riveting article about Amy Bishop, the neuroscience professor who shot her colleagues at the University of Alabama last year, killing three.

It's a fascinating article because of the picture it paints of a killer and it's well worth the time to read. Yet it doesn't really answer the question posed in the title: "What Made This University Scientist Snap?"

Wallace notes the theory that Bishop snapped because she was denied tenure at the University, a serious blow to anyone's career and especially to someone who, apparantly, believed she was destined for great things. However, she points out that the timing doesn't fit: Bishop was denied tenure several months before the shooting. And she shot at some of the faculty who voted in her favor, ruling out a simple "revenge" motive.

But even if Bishop had snapped the day after she found out about the tenure decision, what would that explain? Thousands of people are denied tenure every year. This has been going on for decades. No-one except Bishop has ever decided to pick up a gun in response.

Bishop had always displayed a streak of senseless violence; in 1986, she killed her 18 year old brother with a shotgun in her own kitchen. She was 21. The death was ruled an accident, but probably wasn't. It's not clear what it was, though: Bishop had no clear motive.

Amy had said something that upset her father. That morning they’d squabbled, and at about 11:30 am, Sam, a film professor at Northeastern University, left the family’s Victorian home to go shopping... Amy, 21, was in her bedroom upstairs. She was worried about “robbers,” she would later tell the police. So she loaded her father’s 12-gauge pump-action shotgun and accidentally discharged a round in her room. The blast struck a lamp and a mirror and blew a hole in the wall...

The gun, a Mossberg model 500A, holds multiple rounds and must be pumped after each discharge to chamber another shell. Bishop had loaded the gun with number-four lead shot. After firing the round into the wall, she could have put the weapon aside. Instead, she took it downstairs and walked into the kitchen. At some point, she pumped the gun, chambering another round.

...[her mother] told police she was at the sink and Seth was by the stove when Amy appeared. “I have a shell in the gun, and I don’t know how to unload it,” Judy told police her daughter said. Judy continued, “I told Amy not to point the gun at anybody. Amy turned toward her brother and the gun fired, hitting him.”

Years later Bishop, possibly with the help of her husband, sent a letter-bomb to a researcher who'd sacked her, Paul Rosenberg. Rosenberg avoided setting off the suspicious package and police disarmed it; Bishop was questioned, but never charged.

Wallace argues that Bishop's "eccentricity", or instability, was fairly evident to those who knew her but that in the environment of science, it went unquestioned because science is full of eccentrics.

I'm not sure this holds up. It's certainly true that science has more than its fair share of oddballs. The "mad scientist" trope is a stereotype but it has its basis in fact and it has done at least since Newton; many say that you can't be a great scientist and be entirely 'normal'.

But the problem with this, as a theory for why Bishop wasn't spotted sooner, is that she was spotted sooner, as unhinged, albeit not as a potential killer,by a number of people. Rosenberg sacked her, in 1993, on the grounds that her work was inadaquate and said that "Bishop just didn’t seem stable". And in 2009, the reason Bishop was denied tenure in Alabama was partially that one of her assessors referred to her as "crazy", more than once; she filed a complaint on that basis.

Bishop also published a bizarre paper in 2009 written by herself, her husband, and her three children, of "Cherokee Lab Systems", a company which was apparantly nothing more than a fancy name for their house. There may be a lot of eccentrics in science, but that's really weird.

So I think that all of these attempts at an explanation fall short. Amy Bishop is a black swan; she is the first American professor to do what she did. Hundreds of thousands of scientists have been through the same academic system and only one ended up shooting their colleagues. If there is an explanation, it lies within Bishop herself.

Whether she was suffering from a diagnosable mental illness is unclear. Her lawyer has said so, but he would; it's her only defence. Maybe we'll learn more at the trial.#

H/T: David Dobbs for linking to this.

The Mystery of "Whoonga"

According to a disturbing BBC news story, South African drug addicts are stealing medication from HIV+ people and using it to get high:

'Whoonga' threat to South African HIV patients

"Whoonga" is, allegedly, the street name for efavirenz (aka Stocrin), one of the most popular antiretroviral drugs. The pills are apparantly crushed, mixed with marijuana, and smoked for its hallucinogenic effects.

This is not, in fact, a new story; Scientific American covered it 18 months ago and the BBC themselves did in 2008 (although they didn't name efavirenz.)

Edit 16.00 pm: In fact the picture is even messier than I first thought. Some sources, e.g. Wikipedia and the articles it links to, mostly from South Africa, suggest that "whoonga" is actually a 'brand' of heroin and that the antiretrovirals may not be the main ingredient, if they're an ingredient at all. If this is true, then the BBC article is misleading. Edit and see the Comments for more on this...

Why would an antiviral drug get you high? This is where things get rather mysterious. Efavirenz is known to enter the brain, unlike most other HIV drugs, and psychiatric side-effects including anxiety, depression, altered dreams, and even hallucinations are common in efavirenz use, especially with high doses (1,2,3), but they're usually mild and temporary. But what's the mechanism?

No-one knows, basically. Blank et al found that efavirenz causes a positive result on urine screening for benzodiazepines (like Valium). This makes sense given the chemical structure:
Efavirenz is not a benzodiazepine, because it doesn't have the defining diazepine ring (the one with two Ns). However, as you can see, it has a lot in common with certain benzos such as oxazepam and lorazepam.

However, while this might well explain why it confuses urine tests, it doesn't by itself go far to explaining the reported psychoactive effects. Oxazepam and lorazepam don't cause hallucinations or psychosis, and they reduce anxiety, rather than causing it.

They also found that efavirenz caused a false positive for THC, the active ingredient in marijuana; this was probably caused by the gluconuride metabolite. Could this metabolite have marijuana-like effects? No-one knows at present.

Beyond that there's been little research on the effects of efavirenz in the brain. This 2010 paper reviewed the literature and found almost nothing. There were some suggestions that it might affect inflammatory cytokines or creatine kinase, but these are not obvious candidates for the reported effects.

Could the liver be responsible, rather than the brain? Interestingly, the 2010 paper says that efavirenz inhibits three liver enzymes: CYPs 2C9, 2C19, and 3A4. All three are involved in the breakdown of THC, so, in theory, efavirenz might boost the effects of marijauna by this mechanism - but that wouldn't explain the psychiatric side effects seen in people who are taking the drug for HIV and don't smoke weed.

Drugs that cause hallucinations generally either agonize 5HT2A receptors or block NMDA receptors. Off the top of my head, I can't see any similarities between efavirenz and drugs that target those systems like LCD (5HT2A) or ketamine or PCP (NMDA), but I'm no chemist and anyway, structural similarity is not always a good guide to what drugs do.

If I were interested in working out what's going on with efavirenz, I'd start by looking at GABA, the neurotransmitter that's the target of benzos. Maybe the almost-a-benzodiazepine-but-not-quite structure means that it causes some unusual effects on GABA receptors? No-one knows at present. Then I'd move on to 5HT2A and NMDA receptors.

Finally, it's always possible that the users are just getting stoned on cannabis and mistakenly thinking that the efavirenz is making it better through the placebo effect. Stranger things have happened. If so, it would make the whole situation even more tragic than it already is.

Cavalcante GI, Capistrano VL, Cavalcante FS, Vasconcelos SM, Macêdo DS, Sousa FC, Woods DJ, & Fonteles MM (2010). Implications of efavirenz for neuropsychiatry: a review. The International journal of neuroscience, 120 (12), 739-45 PMID: 20964556