St John's Wort - The Perfect Antidepressant, If You're German

The herb St John's Wort is as effective as antidepressants while having milder side effects, according to a recent Cochrane review, St John's wort for major depression.

Professor Edzard Ernst, a well-known enemy of complementary and alternative medicine, wrote a favorable review of this study in which he comments that given the questions around the safety and effectiveness of antidepressants, it is a mystery why St John's Wort is not used more widely.

When Edzard Ernst says a herb works, you should take notice. But is St John's Wort (Hypericum perforatum) really the perfect antidepressant? Curiously, it seems to depend whether you're German or not.

The Cochrane review included 29 randomized, double-blind trials with a total of 5500 patients. The authors only included trials where all patients met DSM-IV or ICD-10 criteria for "major depression". 18 trials compared St John's Wort extract to placebo pills, and 19 compared it conventional antidepressants. (Some trials did both).

The analysis concluded that overall, St John's Wort was significantly more effective than placebo. The magnitude of the benefit was similar to that seen with conventional antidepressants in other trials (around 3 HAMD points). However, this was only true when studies from German-speaking countries were examined.

Out of the 11 Germanic trials, 8 found that St John's Wort was significantly better than placebo and the other 3 were all very close. None of the 8 non-Germanic trials found it to be effective and only one was close.


Edzard Ernst, by the way, is German. So were the authors of this review. I'm not.

The picture was a bit more clear when St John's Wort was directly compared to conventional antidepressants: it was almost exactly as effective. It was only significantly worse in one small study. This was true in both Germanic and non-Germanic studies, and was true when either older tricyclics or newer SSRIs were considered.

Perhaps the most convincing result was that St John's Wort was well tolerated. Patients did not drop out of the trials because of side-effects any more often than when they were taking placebo (OR=0.92), and were much less likely to drop out versus patients given antidepressants (OR=0.41). Reported side effects were also very few. (It can be dangerous when combined with certain antidepressants and other medications however.)

So, what does this mean? If you look at it optimistically, it's wonderful news. St John's Wort, a natural plant product, is as good as any antidepressant against depression, and has much fewer side effects, maybe no side effects at all. It should be the first-line treatment for depression, especially because it's cheap (no patents).

But from another perspective this review raises more questions than answers. Why did St John's Wort perform so differently in German vs. non-German studies? The authors admit that:

Our finding that studies from German-speaking countries yielded more favourable results than trials performed elsewhere is difficult to interpret. ... However, the consistency and extent of the observed association suggest that there are important differences in trials performed in different countries.

The obvious, cynical explanation is that there are lots of German trials finding that St John's Wort didn't work, but they haven't been published because St John's Wort is very popular in German-speaking countries and people don't want to hear bad news about it. The authors downplay the possibility of such publication bias:

We cannot rule out, but doubt, that selective publication of overoptimistic results in small trials strongly influences our findings.

But we really have no way of knowing.

The more interesting explanation is that St John's Wort really does work better in German trials because German investigators tend to recruit the kind of patients who respond well to St John's Wort. The present review found that trials including patients with "more severe" depression found slightly less benefit of St John's Wort vs placebo, which is the opposite of what is usually seen in antidepressant trials, where severity correlates with response. The authors also note that it's been suggested that so-called "atypical depression" symptoms - like eating too much, sleeping a lot, and anxiety - respond especially well to St John's Wort.

So it could be that for some patients St John's Wort works well, but until studies examine this in detail, we won't know. One thing, however, is certain - the evidence in favor of Hypericum is strong enough to warrant more scientific interest than it currently gets. In most English-speaking psychopharmacology circles, it's regarded as a flaky curiosity.

The case of St John's Wort also highlights the weaknesses of our current diagnostic systems for depression. According to DSM-IV someone who feels miserable, cries a lot and comfort-eats icecream has the same disorder - "major depression" - as someone who is unable to eat or sleep with severe melancholic symptoms. The concept is so broad as to encompass a huge range of problems, and doctors in different cultures may apply the word "depression" very differently.

[BPSDB]

Ernst, E. (2009). Review: St John's wort superior to placebo and similar to antidepressants for major depression but with fewer side effects Evidence-Based Mental Health, 12 (3), 78-78 DOI: 10.1136/ebmh.12.3.78

Klaus Linde, Michael M Berner, Levente Kriston (2008). St John's wort for major depression Cochrane Database of Systematic Reviews (4)

Bigmouth Strikes Again

In the Guardian, Oliver James gets his hands on some mental health statistics. As I have explained before, this rarely ends well. Zarathustra of the really wonderful Mental Nurse blog takes James to to task. Hilarity ensues.

[BPSDB]

In Science, Popularity Means Inaccuracy

Who's more likely to start digging prematurely: one guy with a metal-detector looking for an old nail, or a field full of people with metal-detectors searching for buried treasure?

In any area of science, there will be some things which are more popular than others - maybe a certain gene, a protein, or a part of the brain. It's only natural and proper that some things get of lot of attention if they seem to be scientifically important. But Thomas Pfeiffer and Robert Hoffmann warn in a PLoS One paper that popularity can lead to inaccuracy - Large-Scale Assessment of the Effect of Popularity on the Reliability of Research.

They note two reasons for this. Firstly, popular topics tend to attract interest and money. This means that scientists have much to gain by publishing "positive results" as this allows them to get in on the action -

In highly competitive fields there might be stronger incentives to “manufacture” positive results by, for example, modifying data or statistical tests until formal statistical significance is obtained. This leads to inflated error rates for individual findings... We refer to this mechanism as “inflated error effect”.

Secondly, in fields where there is a lot of research being done, the chance that someone will, just by chance, come up with a positive finding increases -

The second effect results from multiple independent testing of the same hypotheses by competing research groups. The more often a hypothesis is tested, the more likely a positive result is obtained and published even if the hypothesis is false. ... We refer to this mechanism as “multiple testing effect”.

But does this happen in real life? The authors say yes, based on a review of research into protein-protein interactions in yeast. (Happily, you don't need to be a yeast expert to follow the argument.)

There are two ways of trying to find out whether two proteins interact with each other inside cells. You could do a small-scale experiment specifically looking for one particular interaction: say, Protein B with Protein X. Or you can do "high-throughput" screening of lots of proteins to see which ones interact: Does Protein A interact with B, C, D, E... Does Protein B interact with A, C, D, E... etc.

There have been tens of thousands of small-scale experiments into yeast proteins, and more recently, a few high-throughput studies. The authors looked at the small-scale studies and found that the more popular a certain protein was, the less likely it was that reported interactions involving it would be confirmed by high-throughput experiments.

The second and the third of the above graphs shows the effect. Increasing popularity leads to a falling % of confirmed results. The first graph shows that interactions which were replicated by lots of small-scale experiments tended to be confirmed, which is what you'd expect.

Pfeiffer and Hoffmann note that high-throughput studies have issues of their own, so using them as a yardstick to judge the truth of other results is a little problematic. However, they say that the overall trend remains valid.

This is an interesting paper which provides some welcome empirical support to the theoretical argument that popularity could lead to unreliability. Unfortunately, the problem is by no means confined to yeast. Any area of science in which researchers engage in a search for publishable "positive results" is vulnerable to the dangers of publication bias, data cherry-picking, and so forth. Even obscure topics are vulnerable but when researchers are falling over themselves to jump on the latest scientific bandwagon, the problems multiply exponentially.

A recent example may be the "depression gene", 5HTTLPR. Since a landmark paper in 2003 linked it to clinical depression, there has been an explosion of research into this genetic variant. Literally hundreds of papers appeared - it is by far the most studied gene in psychiatric genetics. But a lot of this research came from scientists with little experience or interest in genes. It's easy and cheap to collect a DNA sample and genotype it. People started routinely looking at 5HTTLPR whenever they did any research on depression - or anything related.

But wait - a recent meta-analysis reported that the gene is not in fact linked to depression at all. If that's true (it could well be), how did so many hundreds of papers appear which did find an effect? Pfeiffer and Hoffmann's paper provides a convincing explanation.

Link - Orac also blogged this paper and put a characteristic CAM angle on it.

Pfeiffer, T., & Hoffmann, R. (2009). Large-Scale Assessment of the Effect of Popularity on the Reliability of Research PLoS ONE, 4 (6) DOI: 10.1371/journal.pone.0005996

Everyone is Mentally Ill

There's been a lot of interest over the idea that an "Artificial brain is 10 years away", which is what Professor Henry Markram told the ultra-hip TED conference in Oxford the other day.

That's an amazing idea. But Markram said something else even more astonishing, which, for some reason, has not got nearly as much attention:

"There are two billion people on the planet affected by mental disorder," he told the audience.

Two billion people. One in three.

This was presumably a throw-away remark, something he said in order to emphasise the importance of understanding the brain. But this makes it even more amazing: we have reached the point where no-one bats an eyelid at the idea that mental illness affects one in three people worldwide.

Well, if this is what we believe now, I think we need to stop beating about the bush with numbers like one in four or one in three, and admit that we now are now using "mental illness" as a synonym for "the human condition".

After all, once you pass the point where one in two people have something, you are saying that it's normal and not having it is weird. As I've written before, if you take the evidence seriously, more than 50% of people are indeed "mentally" ill at some point. So let's just say that everyone is mentally ill and have done with it.

Or we could reassess what we mean by "mental illness" and stop medicalizing human suffering. Hey, we can dream.

Major Huntington's Disease Puzzle Solved

Huntington's Disease is a genetic neurological disorder. Symptoms most commonly appear around age 40, and they progress gradually from subtle movement abnormalities to complete loss of motor control and dementia. Psychiatric problems, especially depression and irritability, are also common and may be the first signs. Treatment consists of medications to mask some of the symptoms. Singer Woodie Guthrie is perhaps the disease's best known victim: he ended his days in a mental institution.

Huntington's results from mutations in the gene which makes a protein called Huntingtin (Htt). The symptoms are associated with degeneration of various parts of the brain, most importantly, a deep region called the striatum. These facts have been known for many years, but it's unclear how mutant Htt damages the brain. There are various theories, but they've all faced a serious puzzle - Htt is expressed in all adult human cells, but Huntington's only affects some neurones. Why?

A major new paper claims to have the answer : Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity. It also suggests a promising target for drugs that could prevent the damage from occuring.

The authors assemble evidence showing that mutant Htt kills cells only in conjunction with another protein called Rhes. Crucially, Rhes is only expressed in striatal cells. They found that:

• Rhes binds to Htt, but it binds much more strongly to mutant Htt.
• Causing cells to express both Rhes and mutant Htt leads to cell death, but either by its own does not.
• Rhes mediates the binding of mutant Htt to another protein, SUMO, which causes the mutant Htt to become more soluble and therefore more toxic to cells.

This looks to be a very important addition to the literature on Huntington's. The implication is that a drug which could prevent Rhes from SUMOylating mutant Htt would halt the progression of the disease (although it would presumably not reverse any damage which had already happened.) This is the kind of powerful explanation that neuroscientists who study psychiatric disorders dream about. Maybe in 50 years we will have a similar understanding of schizophrenia - maybe.

Huntington's is a fascinating disorder. The mechanism of inheritance is very distinctive - disease results when a certain section of DNA is too long, and the longer it is, the earlier and more severe the symptoms. And when the pathogenic region is too long, it tends to get even longer during the formation of sperm cells, so the children of fathers with Huntington's often suffer from a more severe, early-onset form. This phenemonon is called genetic anticipation and is unique to Huntingdon's and some similar disorders.

Huntington's is also one of the few disorders which can be accurately diagnosed genetically before the symptoms occur. Anyone at risk of the disease can take a DNA test and know their fate. Perhaps unsurprisingly, most choose not to.

Subramaniam, S., Sixt, K., Barrow, R., & Snyder, S. (2009). Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity Science, 324 (5932), 1327-1330 DOI: 10.1126/science.1172871