The updated NICE guideline for depression is just out. Here is what it has to say about St John’s wort:

Although there is evidence that St John’s wort may be of benefit in mild or moderate depression, practitioners should:
• not prescribe or advise its use by people with depression because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants)
• advise people with depression of the different potencies of the preparations available and of the potential serious interactions of St John’s wort with other drugs.

Funny that. In the last issue of EBMH, Edzard Ernst, the professor of complementary medicine who has become the bête noire of the alternative medicine crowd was less dismissive. Reviewing the latest Cochrane update he concludes that there is now plenty of evidence demonstrating that SJW is an effective antidepressant and if you can avoid herb-drug interactions, it may be safer than conventional drugs. So why don’t we recommend SJW for depression?

I have written about SJW here before and was less than complimentary (ouch!). My scepticism was similar to the NICE position: you can’t be sure what you are getting, and patients thinking that it’s not really a drug mix it with prescription medication and run into trouble. Perhaps, however, there is more to it than that. Given the rather murky history of clinical trials and marketing with conventional antidepressants and the often marginal benefit over placebo it does seem as though when it comes to evidence we hold St John’s wort to a higher standard. Trawl through the rapid responses of a trial involving SJW and you will find a degree of nit-picking that is rarely seen with the SSRIs. This type of reader or reviewer bias is not much discussed and competing interest statements rarely include declarations of inherent prejudice. In this editorial for Clinical Evidence, Professor Ernst criticises the knee-jerk assumption that if a clinical trial of a complementary medicine shows efficacy it must be a flawed trial. So is St John’s wort being treated unfairly? The answer, I think, has to be yes.

More antidepressants please…and bump up the Ritalin too. That seems to be the suggestion from this study published by the National Bureau of Economic Research in the US, making a link between new drug treatments for depression and ADHD and falling crime rates (Hat tip: The Economist).

Since the 1990s violent crime rates have declined markedly (no, it’s true, really), especially in the US. Criminologists have struggled to explain the trends as the usual suspects seem to have had little impact. So enter the economists with their alternative explanations, such as Steven Levitt (he of Freakonomics fame) presenting evidence that legalizing abortion in the 1970s led to a decline in the number of young people at risk of criminality, thus reducing crime rates.

In their provocative paper, A Cure for Crime?, Dave Marcotte and Sara Markowitz use data on international drug sales and crime rates as well as more detailed US data from the National Comorbidity Study (showing that in those with a mental disorder the percentage receiving treatment has increased from 20 to 33%) and national prescribing rates to show that ‘the countries with the largest declines in crime rates in the 1990s were almost exclusively those with the fastest growth in SSRI sales’. Details of the analysis are in an ungated preliminary version of the paper here. To control for overall improvements in health care they also looked at the impact of the non-psychotropic medicines, statins and COX-2 inhibitors which have also seen a rapid growth in prescriptions, but here there was no effect. They found that that increased prescribing of psychiatric drugs, notably SSRIs and stimulants (Ritalin), were associated with a reduction in violent crime and go on to conclude:

“Our evidence suggests that, in particular, sales of new generation antidepressants and stimulants used to treat ADHD are associated with rates of violent crime, with weaker evidence that anti-psychotic medications played a role in declining crime rates. The magnitude of the elasticities estimated here are clearly small. We estimate that a one percent increase in the total prescription rate is associated with a 0.051 percent decrease in violent crimes. To put this in perspective, doubling the prescription rate would reduce violent crimes by 5 percent, or by about 27 crimes per 100,000, at the average rate of 518 crimes per 100,000 population. While doubling the prescription rate seems like a large change, it has been estimated that 28 percent of the U.S. adult population in any year has a diagnosable mental or addictive disorder, yet only 8 percent seeks treatment (USDHHS 1999). Doubling the treatment rate would still leave a substantial portion of the ill untreated.

From the beginning to end of our panel, prescriptions per visit increased by 41 percent. Our elasticity estimates imply that this would reduce the total number of violent crimes committed by about 35,000. In fact, the total number of violent crimes reported to police declined by 300,000 during the period. Our estimates imply that just under 12 percent was due to expanded mental health treatment.”

Medical journals tend be dismissive of natural experiments and ecological studies such as this, considering them pretty weak evidence. But given that questions like this are never going to be answered by randomized controlled trials, if the methods are robust some freakonomic epidemiology may be just what we need.

Can you believe what you read in a medical journal? Probably not, as many if not most research findings turn out to be false. Poor research design and underpowered studies are part of the problem but looming large in the background is the spectre of publication bias.

No one doubts that negative studies should be published, yet it remains the case that they struggle to get into journals. By negative studies I mean studies that don’t show a statistically or clinically significant effect, or where a new treatment is more effective than standard treatment or placebo but has intolerable or dangerous adverse effects. Much of the blame has been heaped upon those unscrupulous drug companies callously suppressing unfavourable data. But before we all climb up on our collective high horse you should read this month’s Editor’s Choice (free to access) in Evidence–Based Mental Health.

In his personal account of his struggle to publish negative data on the drug lamotrigine, Nassir Ghaemi points the finger at not just the pharma industry, but at the FDA, journal editors and the peer review process itself. A Boston psychiatrist, he speaks as an insider having sat on an advisory board for GlaxoSmithKline as well as the editorial board of the journal Bipolar Disorders (he also writes an entertaining blog, Mood Swings). The contemptuous tone of the rejection letters will be familiar to anyone who’s submitted a paper, as will the contradictory reasons for refusal.

We now have clinical trials registration – requiring that all results end up somewhere in the public domain – which is clearly a good thing. There are also journals such as BMC Research Notes and the Journal of Negative Results in BioMedicine that are specifically aiming to publish negative studies. However the fact that a paper attempting to address publication bias should itself fall victim to that bias indicates that this is a problem that won’t go away.

That drug companies play fast and loose with study data is hardly news. It’s a widely-acknowledged problem that has been highlighted particularly with antidepressant trials where the advantage over placebo is often equivocal. Not before time, someone has decided to draw a line: “Deception through concealment is no trivial offence”, says the director of IQWiG – the German version of NICE – as he accuses Pfizer of concealing data about the antidepressant, reboxetine.

IQWiG (The Institute for Quality and Efficiency in Health Care) has ruled that reboxetine has no proof of benefit. They report that the drug has been tested in at least 16 trials but in 9 of them key information is not reported so they are unable to evaluate the effect of the antidepressant on 3000 of the 4600 patients enrolled. What are the implications of their ruling? The watchdog provides an assessment that is used to inform which medical treatments can be reimbursed through the public health insurance system in Germany – Europe’s largest market for drugs.

A rather sniffy spokesman for Pfizer told the BMJ that IQWiG is not a ‘regulatory authority’ but a ‘private institute’ and that there was no obligation to provide them with information. This seems at odds with Pfizer’s own policy on disclosure: “in all cases study results are reported by Pfizer in an objective, accurate, balanced and complete manner and are reported regardless of the outcome of the study or the country in which the study was conducted.”

Reboxetine itself has had a bit of a mauling of late. The Lancet’s recent comparative meta-analysis of 12 newer antidepressants put reboxetine at the bottom of the pile both in terms of efficacy and tolerability. It’s also not available in the US as the FDA turned down the application for a license for reasons which are still unclear. Paradoxically, if this license had been granted current US legislation would have required full disclosure of all the trial data. IQWiG is now calling for a similar European Union-wide legal obligation to publish all trial results as clearly self-regulation by the industry is not working. Corrado Barbui, writing in EBMH, made the same point back in 2007. Isn’t it time to get on with it?

Trying to find evidence to guide practice in mental health can be perplexing at the best of times. Take antidepressants for example: seemingly prescribed by the bucketload (170 million prescriptions issued per year in the US, 31 million in the UK) many GPs and psychiatrists will admit that when it comes to choice of drug, more often than not it’s a case of ‘suck it and see’. We may have a raft of sophisticated neuroimaging techniques but we still struggle to explain how they work and when it comes to predicting response – well that’s anybody’s guess.

These days, we view pharma-funded trials with a jaundiced eye, particularly when they are promoted by ‘key opinion leaders’ (to see one KOI meet his nemesis, take a look at the Carlat Psychiatry Blog), so I would recommend this month’s Editor’s Choice (that means it’s free to access) in Evidence-Based Mental Health. Simon Hatcher casts a critical gaze over the STAR*D trial, the largest study of treatments for depression ever undertaken. It is one of the new breed of pragmatic trials – studies that assign ‘real world’ patients to licensed drugs aiming to assess their effectiveness (do they work in real life?) rather than efficacy (do they work in ideal conditions?). Publicly funded, at a cost of $35 million, and enrolling almost 3000 participants STAR*D really is, as Hatcher states, the 300lb gorilla of antidepressant trials. So what does STAR*D tell us? Well, read the review to find out but it’s clear that quality is just as important as quantity.

The benefits of St John’s wort (SJW) have been widely reported this week following the publication of this study. It’s not, as some articles suggest, a new trial but actually an update of a Cochrane systematic review and meta-analysis. The review is comprehensive, with the addition of some big recent RCTs, and the authors have restricted the inclusion criteria to major depression. The results reinforce those of earlier reviews: SJW is as effective as standard antidepressants in mild and moderate depression with the benefit of fewer side effects.

Perhaps the most interesting finding is that studies from German-speaking countries show much more favourable results. In fact taking out the German studies from the meta-analysis removes any benefit of SJW over placebo. It’s not easy to explain this difference – you can insert your own cultural jokes here. What is notable is that the German trials predominantly recruited from private practices in primary care with a long tradition of prescribing SJW. This contrasts with the remainder where studies were carried out in academic or hospital settings where SJW is not licensed as a drug. Despite matching inclusion criteria there may have been differences between the types of patient entering the trials (selection bias). Andere Länder, andere Sitten.

So given this ‘natural’ alternative why don’t I recommend SJW to people I see with depression? Well in the UK it’s not licensed as a medicine but sold as a dietary supplement, and comes over the counter in a variety of formulations: pills, potions, lotions – you might even to able to smoke it. That means it can be difficult to know what you are getting and dosages in this review varied from 240 to 1800 mg per day. The active ingredient and mechanism of action is still unknown – not that we really understand how standard antidepressants work either. The other concern is the potential for drug interactions. SJW stimulates those liver enzymes that break down medicines such as warfarin, HIV drugs and oral contraceptives rendering them ineffective. Combining it with other antidepressants can also have nasty effects: I had a near miss with a woman starting on the antidepressant sertraline, who hadn’t admitted to SJW use as it was a ‘herb’ she was taking for migraine. So it may be a plant extract but it is certainly not innocuous.

You might think so looking at newspaper reports of a study examining the effect of paroxetine on sperm quality. It’s well known that antidepressants, the SSRIs in particular, can have sexual side effects: notably a drop in libido and delayed orgasm. In fact the SSRIs have been used pretty effectively as a treatment for premature ejaculation. Sexual dysfunction is one thing but infertility is another, so what does this study by a team of New York urologists actually tell us?

Bear in mind that this is a very small before and after study with no control group, which might explain why it hasn’t appeared in a peer-reviewed publication but did make the BBC News. Thirty-five healthy (and presumably not depressed) men were given paroxetine at doses of up to 30mg daily for 5 weeks. The researchers looked at the men’s semen at baseline and then four weeks into the study. Sperm numbers, motility and morphology were unaffected but the level of damaged sperm DNA rose from a mean of 14% to 30%. Clinically significant? A good question and one that’s debatable according to Allan Pacey, Senior Lecturer in Andrology at the University of Sheffield. More and better research needed seems to be the message. Should this study change practice? I don’t think so. A long list of drugs, both prescribed and recreational, are known to affect sperm quality. What’s reassuring is that most men seem to produce enough of the stuff for their fertility to remain unaffected and sperm quality usually returns to normal once the drug is withdrawn.