Neurology Center

The proportion of Americans using antidepressants in a given year nearly doubled from 5.8% in 1996 to 10.1% in 2005, according to a paper just published: National Patterns in Antidepressant
Medication Treatment, by Mark Olfson and Steven Marcus.

That means about 15 million more Americans were medicated in '05 than a decade previously. A huge increase in anyone's book. But the doubling in antidepressant use is not the only interesting result in this paper. In no particular order, here are some other fun facts -

• Women are twice as likely to use antidepressants as men (female 13.4% vs male 6.7% in 2005); the ratio was the same in 1996. Studies consistently find that Western women are about twice as likely to report suffering from depression and anxiety disorders as men are. But these kinds of studies rely on self-report so this could merely mean that women are more willing to talk about their problems. This data suggests that they also seek treatment about twice as often.
  
• The peak age bracket for antidepressants is 50-64, with 15.5% yearly use. This is more than double the rate in the 18-34 bracket. This surprised me, maybe because of the influence of books like Prozac Nation (tagline - "Young and Depressed in America"). So, it looks like the increasing use of antidepressants is not because younger people, having grown up in the "Prozac Era", are more accepting of them.
  
• Antidepressants are a white thing - 12.0% of whites take them vs. about 5% of blacks and Hispanics. But it would be interesting to see a regional breakdown here. Are blue-state or red-state whites more likely to be medicated?
• Family income was not correlated with antidepressant use, but the unemployed were twice as likely to use antidepressants: 22% in '05. This might be because unemployment is bad for your mental health, or because mental illness is bad for your employment prospects. Or both.
  
• One of the questions in the survey asked people to rate their own mental health. Over 90% of Americans said it as "good", "very good" or "excellent" - including 80% of antidepressants users. This really surprised me, and suggests that these drugs are being prescribed to people who are not, overall, very unwell.
  
• The % of antidepressant users also using an antipsychotic drug rose from 5.5% to 8.9% in 2005. Given that the number of users also doubled, this means the number of Americans using an antipsychotic as well as an antidepressant increased by a factor of more than 3. This is worrying since antipsychotics are generally the worst psychiatric drugs in terms of side effects. While there is evidence that some of the newer antipsychotics can be of use in depression as an add-on to antidepressants, this is controversial and it's not clear that they're any better than the older alternatives, such as lithium.
  

Last week, I wrote about a paper finding that the mosquito repellent chemical, DEET, inhibits an important enzyme, cholinesterase. If DEET were toxic to humans, this finding might explain why.
But it isn't - tens of millions of people use DEET safely every year, and there's no reason to think that it is dangerous unless it's used completely inappropriately. That didn't stop this laboratory finding being widely reported as a cause for concern about the safety of DEET.

This is putting the cart before the horse. If you know that something happens, then it's appropriate to search for an explanation for it. If you have a phenemonon, then there must be a mechanism by which it occurs.

But this doesn't work in reverse: just because you have a plausible mechanism by which something could happen, doesn't mean that it does in fact happen. This is because there are always other mechanisms at work which you may not know about. And the effect of your mechanism may be trivial by comparison.

Caffeine can damage DNA under some conditions. Other things which damage DNA, like radiation, can cause cancer. But the clinical evidence is that, if anything, drinking coffee may protect against some kinds of cancer (previous post). There's a plausible mechanism by which coffee could cause cancer, but it doesn't.

Medicine has learned the hard way that while understanding mechanisms is important, it's no substitute for clinical trials. The whole philosophy of evidence-based medicine is that treatments should only be used when there is clinical evidence that they do in fact work.

Unfortunately, in other fields, the horse routinely finds itself behind the cart. An awful lot - perhaps most - of political debate consists of saying that if you do X, Y will happen, through some mechanism. If you legalize heroin, people will take more of it, because it'll be more available and cheaper. If you privatize public services, they'll improve, because competition will ensure that only the most efficient services survive. If you topple this dictator, the country will become a peaceful democracy, because people like peace and democracy. And so on.

These kinds of arguments sound good. And they invite opponents to respond in kind: actually, legalizing heroin is a good idea, because it will make taking it much safer by eliminating impurities and infections... And so the debate becomes a case of fantasizing about things that might happen, with the winner being the person whose fantasy sounds best.

If you want to know what will happen when you implement some policy, the only way of knowing is to look at other countries or other places which have already done it. If no-one else has ever done it, you are making a leap into the unknown. This is not necessarily a bad thing - there's a first time for everything. But it means that "We don't know" should be heard much more often in politics.

It's a cliché, but it's true - "schizophrenia genes" are the Holy Grail of modern psychiatry.

Were they to be discovered, such genes would provide clues towards a better understanding of the biology of the disease, and that could lead directly to the development of better medications. It might also allow "genetic counselling" for parents concerned about their children's risk of schizophrenia.

Perhaps most importantly for psychiatrists, the definitive identification of genes for a mental illness would provide cast-iron proof that psychiatric disorders are "real diseases", and that biological psychiatry is a branch of medicine like any other. Schizophrenia, generally thought of as the most purely "biological" of all mental disorders, is the best bet.

With this in mind, let's look at three articles (1,2,3) published in Nature last month to much excited fanfare along the lines of 'Schizophrenia genes discovered!' All three were based on genome-wide association studies (GWAS). In a GWAS, you examine a huge number of genetic variants in the hope that some of them are associated with the disease or trait you're interested in. Several hundred thousand variants per study is standard at the moment. This is the genetic equivalent of trying to find the person responsible for a crime by fingerprinting everyone in town.

The Nature papers were based on three seperate large GWAS projects - the SGENE-plus, the MGS, and the ICS. In total, there were over 8,000 schizophrenia patients and 19,000 healthy controls in these studies - enormous samples by the standards of human genetics research, and large enough that if there were any common genetic variants with even a modest effect on schizophrenia risk, they would probably have found them.

What did they find? On the face of it, not much. The MGS(1) "did not produce genome-wide significant findings...power was adequate in the European-ancestry sample to detect very common risk alleles (30–60% frequency) with genotypic relative risks of approximately 1.3 ...The results indicate that there are few or no single common loci with such large effects on risk." In the SGENE-plus(2), likewise, "None of the markers gave P values smaller than our genome-wide significance threshold".

The ISC study(3) did find one significantly associated variant in the Major Histocompatability Complex (MHC) region on chromosome 6. The MHC is known to be involved in immune function. When the data from all three studies were pooled together, several variants in the same region were also found to be significantly associated with schizophrenia.

Somewhat confusingly, all three papers did this pooling, although they each did it in slightly different ways - the only area in which all three analyses found a result was the MHC region. The SGENE team's analysis, which was larger, also implicated two other, unrelated variants, which were not found in other two papers.

To summarize, three very large studies found just one "schizophrenia gene" even after pooling their data. The variant, or possibly cluster of related ones, is presumably involved in the immune system. Although the authors of the Nature papers made much of this finding, the main news here is that there is at most one common variant which raises the relative risk of schizophrenia by even just 20%. Given that the baseline risk of schizophrenia is about 1%, there is at most one common gene which raises your risk to more than 1.2%. That's it.

So, what does this mean? There are three possibilites. First, it could be that schizophrenia genes are not "common". This possibility is getting a lot of attention at the moment, thanks to a report from a few months back, Walsh et al, suggesting that some cases of schizophrenia are caused by just one rare, high-impact mutation, but a different mutation in each case. In other words, each case of schizophrenia could be genetically almost unique. GWAS studies would be unable to detect such effects.

Second, there could be lots of common variants, each with an effect on risk so tiny that it wasn't found even in these three large projects. The only way to identify them would be to do even bigger studies. The ISC team's paper claims that this is true, on the basis of this graph:

They took all of the variants which were more common in schizophrenics than in controls, even if they were only slightly more common, and totalled up the number of "slight risk" variants each person has.

The graph shows that these "slight risk" markers were more common in people with schizophrenia from two entirely seperate studies, and are also more common in people with bipolar disorder, but were not associated with five medical illnesses like diabetes. This is an interesting result, but these variants must have such a tiny effect on risk that finding them would involve spending an awful lot of time (and money) for questionable benefit.

The third and final possibility is that "schizophrenia" is just less genetic than most psychiatrists think, because the true causes of the disorder are not genetic, and/or because "schizophrenia" is an umbrella term for many different diseases with different causes. This possibility is not talked about much in respectable circles, but if genetics doesn't start giving solid results soon, it may be.

Edit: I missed it at the time but the great Prof. David Colhoun wrote an extremely good piece about this study.


Purcell, S., & et Al (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder Nature DOI: 10.1038/nature08185

Shi, J., & et Al (2009). Common variants on chromosome 6p22.1 are associated with schizophrenia Nature DOI: 10.1038/nature08192

Stefansson, H., & et Al (2009). Common variants conferring risk of schizophrenia Nature DOI: 10.1038/nature08186

Over at Bad Science, Ben Goldacre decries an article about a spurious "study", lifted straight from a corporate press-release, in his own newspaper The Guardian:

On Monday we printed a news article about a “report” “published” by Nuffield Health, headlined “No sex please, we’re British and we’re lazier than ever”. “This is the damning conclusion of a major new report published today,” says the press release from Nuffield ... I asked Nuffield’s press office for a copy of the new report, but they refused, and explained that the material is all secret. The Guardian journalist can’t have read it either. I don’t really see how this “report” has been “published”, and in all honesty, I wonder whether it even exists, in any meaningful sense, outside of a press release.

Nuffield Health are the people who run private hospitals and clinics which you can’t afford....the Guardian gave free advertising to Nuffield, for their unpublished published “report”, which nobody even read, in exchange for 370 words of content. This is endemic, and it creeps me out.

The Templeton Foundation is offering $4,000,000 to fund research into "Positive Neuroscience". The idea seems to be put some neuro into Positive Psychology. Aspiring neuroscientists are invited to submit proposals for

[BPSDB]

Modern psychiatry is an alphabet soup of acronyms. Sometimes it seems like there are almost as many as there are drugs. This can be confusing. So, here's a quick guide to what they really mean.

Please add any of your own in the comments!

SSRI - Sexual Stimulation Required Increased(*)
Also, Suicides? Suppress Report Immediately!(*)
Also, Stopped Suddenly - Regret Imminent?(*)

NRI - No Real Impact?(*)
Also, Nix Relevant Information(*)

NASSA (mirtazapine) - Never Again Slim; Sleep Alot.(*)
Also, Nighttime, And Strange Sights Abound(*)

TCA - The Classic Antidepressants(*)
Also, Toxicity - Cardiac Arrests(*)

ECT - Effective, Cheap Treatment(*)
Also Erases Childhood Thoughts?(*)

VNS - Very Nebulous Science(*)
Also, Very New Snakeoil?

fMRI - Future Marketable Research Initiative(*)

Watch out! The BBC report that -

Deet bug repellent 'toxic worry'

According to CNN, the kids in Hong Kong are all taking ketamine ("the horse tranquilizer") nowadays - although we're not given much in the way of statistics.

Ketamine is a fascinating molecule. On the street, it's a drug, naturally. High doses produce a state of dissociative unconciousness affectionately called the "K-hole", while lower doses have a sedative and mild hallucinogenic effect which goes well with dancing, allegedly. It's also used medically as an anaesthetic.

In psychiatry, ketamine is three things: a drug of abuse, an antidepressant, and a way to mimic schizophrenia. Or rather, there are people who think of ketamine as each of these things. It seems somewhat unlikely that it could be all three at once. You don't treat depression by causing schizophrenia, and people don't deliberately give themselves psychosis, even temporarily.

Yet a journal could publish a paper about using ketamine as a model of schizophrenia, and another paper about its supposed antidepressant effects a few pages later, and few people would bat an eyelid. This is because most researchers interested in schizophrenia wouldn't read the depression paper, and vice versa.

Partly this is because, like all scientists today, psychopharmacologists tend to stick to their own research niches. But it's also a symptom of the fact that no-one's job is to study ketamine, as such. We study diseases, rather than drugs, which can lead to theories which fly in the face of half of the evidence. (See this post for another example.)

The evidence that ketamine can treat depression essentially consists of one study from 2006 (ref) and a pilot study from the same group (ref), plus a handful of case reports. Zarate et al reported that a single injection with a moderate dose of ketamine (0.5mg/kg) had a dramatic antidepressant effect in a large proportion of depressed patients, and that this lasted at least a week in some cases.

This paper sparked a flurry of interest into ketamine and depression, with animal studies and brain scans galore trying to explain how it might work. Maybe ketamine does have an antidepressant effect. But if it does, it's a miracle drug, acting much faster than any other. You need to take Prozac for several days or weeks before feeling any benefit. A single injection does diddly-squat.

The dramatic benefits seen in this study may have been simply placebo effects: the patients expected to feel much better after taking this exciting new drug, so they said they did. The study was placebo controlled, true. When people got injections of salt water, they didn't report any benefit. In theory, it was double blind - neither the patients nor the doctors knew whether they were getting ketamine or water. But you'll know when you've been injected with 0.5mg/kg ketamine. You get high. That's why people take it. The study can't really be called double blind.

To their credit, Zarate et al did acknowledge this, and suggested that in future ketamine could be compared to another drug which produces noticeable effects. But they really should have done that to begin with. This is not a criticism of these researchers - what they did was par for the course in psychopharmacology. Unfortunately.

The idea that ketamine intoxication mimics schizophrenia (ref) is an interesting one, and it may well be a model of some of the symptoms. My only ketamine experience doesn't really fit with either the schizophrenia or the antidepressant theory, however. I was slightly depressed before I took it, and it made me feel much worse. I didn't hear any voices, though. On the other hand, a good friend became addicted to the stuff for several months, and still craves it. To each his own...