There's a saying in Spanish that roughly translated says "Calamities never arrive alone". Following John McCain's statement on the "strong" evidence for a link between vaccines and autism, which Charlotte Schubert blogged about, the ruling in the case of Hannah Poling is a second calamity that is bound to add more fuel to a debate that hasn't been particularly productive.

The US government's decision to settle and agree to pay Hannah, who has autistic symptoms, for her care has been immediately heralded as a victory for supporters of the vaccine-autism link, even though officials have been careful to clarify that they didn't concede that vaccines cause autism.

The government can continue to clarify their position until they go blue in the face but, unfortunately, this ruling is bad news for the science that has debunked the autism-vaccines link, for the cost of health care in the US (which is bound to feel the effect of more settlements of this sort, if this case is accepted as precedent), and for herd immunity (the effectiveness of which may decrease if too many kids in a given pupulation stop being vaccinated).

Posted by Juan Carlos Lopez at 04:01 PM | Permalink | Comments (1)

Today's paper in PLoS Medicine reporting on a meta-analysis of clinical data on SSRI inhibitors for the treatment of depression really made a splash.

The article, by Irving Kirsch and his colleagues, showed that, when you look at data from 35 randomized clinical trials testing the efficacy of four of these "new-generation antidepressants", the only differences between the drug and the placebo groups are seen in severely depressed patients.

Although this is not the first time that a meta-analysis has provided evidence against the eficacy of SSRIs, it is perhaps the largest study of its kind available so far, immediately fuelling existing concerns about their widespread use in medical practice.

Not unexpectedly, the companies that sell the drugs have already issued statements supporting the efficacy of their products, pointing out that the meta-analysis didn't look at all of the available data. It wasn't clear, however, if the companies were referring to postmarketing surveillance data, something that is entirely possible, as the paper was based strictly on data received by the US Food and Drug Admnistration (FDA) before approval of the drug.

In any case, this is not the first time that we experience this scenario. You can bet that we will now start hearing accusations of negligence against the FDA for approving medicines that don't work. The public image of pharma companies will be further tarnished by negative claims against their products. Psychiatrists will have to reassure their patients, trying to encourage them to remain compliant. Iin fact, some associations of psychiatrists have already issued statements urging patients not to stop taking their medications until they discuss the situation with their doctors.) And people with depression? Well, I guess they'll have every reason to be depressed.

Now, is it really the case that these drugs don't work but in a small subset of patients? These drugs are globally available, and several world regions have their own regulatory agencies, each of which carries its own analysis of efficacy before approving a drug. Are we supposed to accuse not only the FDA, but every other regulatory agency of not doing a good job making sure that a drug works? It's possible, but unlikely.

OK, let's say that the lack of efficacy could not be detected with the data submitted to the regulators, but only with the large number of patients that you look at when you do a meta-analysis. Should the regulatory agencies then ask for much larger (and therefore much more expensive) trials before approving an antidepressant? Maybe, but then it might be too harsh to use a post hoc analysis that had the opportunity to look at data from at least four different companies to then rebuke the FDA for their approval of the drug or each of the individual companies for their trial design.

To my mind, the key issue now is to see what the regulatory agencies are going to do after the publication of these findings. Will they look at postmarketing surveillance data to try to confirm or rebut the alleged lack of efficacy? Will they modify their approval of the drug so that it is only prescribed to the small subset of patients in whom an effect was observed? In several Nature Medicine Editorials, some of which are here (1, 2, 3, 4, 5), we have been critical of the FDA's leadership and commented on the need of the agency to regain the confidence of consumers. So, the publication of the PLoS Medicine paper should not necessarily be construed as a new embarrassment for the FDA, but as a fresh opportunity for the agency to show that it can respond to public concerns, and handle the situation efiiciently and wisely.

Posted by Juan Carlos Lopez at 03:39 PM | Permalink | Comments (2)

It's always gratifying when something you published in your journal is regarded by others as an important contribution. This report in yesterday's New York Times discusses extensively the trial we published last year showing that an agonist of metabotropic glutamate receptors was beneficial in people with schizophrenia.

It's a shame that the NYT didn't identify Nature Medicine as the place in which the original paper was published, but so be it. I'm delighted to see that the findings are receiving the attention they deserve.

Posted by Juan Carlos Lopez at 04:35 PM | Permalink | Comments (2)

A report last week stated that, according to the US Health and Human Services Department, advocates of the idea that vaccines are linked to autism will join neurologists and other health professionals as members of the Interagency Autism Coordinating Committee, a new panel that will recommend areas for autism research.

If the vaccines-autism link has been repeatedly proven to be wrong, and even the Institute of Medicine, an independent organ that advises the US government on health issues, has urged scientists to look elsewhere for the causes of autism, what's the point of including supporters of such a link, other than to appease the advocacy groups?

I hope I'm wrong, but being inclusive for the sake of political correctness doesn't strike me as the right way to tackle a problem as serious as autism.

Posted by Juan Carlos Lopez at 03:26 PM | Permalink | Comments (4)

It doesn't happen everyday that a fellow editor writes an Op-Ed column for The New York Times, but my colleague Sandra Aamodt, Chief Editor of Nature Neuroscience, has done just that. Well done, Sandra! I'll let you do the talking, simply providing a link to your contribution.

Posted by Juan Carlos Lopez at 02:07 PM | Permalink | Comments (0)

A while ago, I had a chat with Phil Campbell, who just arrived in New York after dining with royalty., and he told me something extraordinary.

We started talking about cognitive enhancement -- taking drugs to improve your cognitive skills. Of course, drugs for conditions such as ADHD and narcolepsy have been used by some people for some time, but data on their efficacy are scarce and not well controlled. The fascinating thing is that it seems that Phil heard from a reliable source that, if you wanted, you could set up a clinical trial specifically designed for a putative cognitive enhancer here in the USA. In other words, the FDA would not get on your way if your clinical trial was not for a drug aimed at curing disease, but designed to enhance your natural abilities.

I'm frankly surprised about it and wonder if this is really the case. Can anybody out there confirm or deny this? And if this is true, what would be a reliable endpoint in a trial of a cognitive enhancer? Maybe that's why you don't hear about companies going after this dream; because one doesn't have a meaningful endpoint.

One thing I can tell you: the day we have a safe cognitive enhancer, I'll be the first one to buy it.

Posted by Juan Carlos Lopez at 08:53 PM | Permalink | Comments (2)

Last month, my friend Jose Obeso invited me to a think-tank meeting on Parkinson Disease in Pamplona. It wasn't July, which is when you get a chance to run with the bulls. But even if it had been, Jose told me that he wouldn't let me run with them. "Too dangerous", he said. He also explained to me that you simply can't run all the way from the encierro (the point from which they release the bulls) to the plaza.

Broadly speaking, there are three stretches, and you have to pick one: 1) the beginning, which is uphill, making it harder for the bulls even though they are fresh; 2) the middle one, quite tricky owing to the curves and how crowded it is; and 3) the end, straight and flat, although the bulls are tired by the time they get to it.

I don't want to push the analogy too far, as those who know me are aware of how much I like to make fun of bad analogies, but I'd say that the meeting also released three bulls that people interested in Parkinson ought to fight. I won't dwell on them in detail, as there will be an article coming out of the think tank, and I wouldn't want to steal their thunder but, in broad terms, they are:

1) The definition of Parkinson -- When we talk about the disease, is it just one disease? Is early-onset Parkinson the same thing as late-onset? Are the genetic forms the same as the early-onset forms? Are genetic forms even the same as the idiopathic forms? There are several other ways to slice the Parkinson pie, and it wouldn't be a bad idea to make sure that we are talking about the same disease before trying to solve it.

2) Models of Parkinson -- A lot of the work on oxidative damage (a favorite idea in the Parkinson field) has been done in cultured cells, and people are painfully aware of the shortcomings of the chemical models, including the use of MPTP. It seems that the field is in desperate need of new models, particularly those that exploit the insights from genetic forms of Parkinson.

3) Mechanisms in Parkinson -- There seems to be a deep disconnection between the solid data coming out of the genetic analyses and what's going on at the level of the mitochondria in the dopaminergic neurons. In a nutshell, Parkinson remains a mechanistic black box. And if this is the case even when we have a good genetic starting point, the situation regarding idiopathic forms of the disease is even more bleak.

After all, maybe the analogy isn't too bad, because I'm certainly not discovering anything those in the field know already. Alas, it would seem that many people in the field do prefer running away from these three bulls rather than chasing them. One of my readings of the meeting was that, until these issues aren't tackled head on, the Parkinson field will not see the breakthroughs it's been looking for.

Posted by Juan Carlos Lopez at 10:53 AM | Permalink | Comments (1)

What's the drug of choice in your city? Cocaine? Methamphetamine? Or a simple cup of java?

Turns out it's a lot easier to find out than lurking in alleyways or crashing hipster parties. Scientists from Oregon State University have figured out a way to test an entire city for its drug use — legal and illegal.

The scientists sampled about a teaspoon of water from the sewers — because that's eventually where what people consume ends up — of 10 American cities and tested them for 15 different drugs.

The results, which they presented the Amercan Chemical Society meeting in Boston on Tuesday, are not all that surprising in the end. Here are a few gems:

Most Americans are not too wild and crazy, and their drug of choice is caffeine. People in the midwest are a little more conservative and don't seem to indulge too much in meth use. One city with a heavy gambling industry — Las vegas, anyone? — shows meth levels five times higher than other cities.

I have no doubt New York has its share of drug use, what with all our models, actors and and hyperactive investment bankers. How do you think your city would fare?

Posted by Apoorva Mandavilli at 03:35 PM | Permalink | Comments (0)

The article on Lesch-Nyhan syndrome in this week's The New Yorker (An Error in the Code) caught my attention. It's a shame the magazine didn't publish it online, as it's worthwhile reading.

Its subtitle is "What can a rare disorder tell us about human behavior?" Not a lot, I'm afraid.

In a nutshell, people with Lesch-Nyhan lack the enzyme HRPT, which is important for purine metabolism. Patients experience damage to their kidneys, joints and other organs. But the most evident feature of the disease is the patients' drive to inflict physical damage on themselves -- what somewhere in the article is referred to as "the imp of the perverse" in reference to a phrase by Edgar Allan Poe.

It won't come as a surprise that, whereas the kidney and joint damage can be managed in people with the condition, the behavioral problems cannot, at least not very effectively -- as Lesch-Nyhan patients tend to bite their fingers and lips off, restraining their hands and removing their teeth are among the most commonly used ways to keep them from doing so.

What can this grim phenotype tell us about human behavior? A scientist who studies the disorder is quoted as saying that "We all do things that are bad for us... Many people bite their fingernails... There are people who chew their lips nervously. Now let's turn up the volume a little: some people bite their cuticles". And if you keep on "turning up the volume", he argues, you end up with people who bite their fingers to the bone. Surely this is an oversimplification. And even if it's not an oversimplification, it certainly doesn't go too far towards helping us understand what's wrong with these patients.

Another thing that captured my attention was the fact that doctors in Japan and France have managed to eliminate self-mutilation in some of these patients by using deep brain stimulation (DBS), a technique that has yet to be approved for this disease in the U.S. Considering the recent report from American scientists of the man who "woke up" as a result of DBS after spending six years in minimally conscious state, I wonder what's keeping a trial with Lesch-Nyhan patients from starting.

The last thing that caught my attention was the fact that, even though we know what gene is mutated in the disease (HRPT), what part of the brain seems to be affected (the globus pallidus and other parts of the basal ganglia), and what neurotransmitter is reduced (dopamine), there are very few people studying Lesch-Nyhan. During my tenure at Nature Medicine, for example, I don't recall reading a single submission on this topic. So, for those young scientists who are looking for a niche to get their career started (and for those who are tired of drowning in the swamp of Alzheimer or Parkinson disease), Lesch-Nyhan does not look like a bad possibility at all.

Posted by Juan Carlos Lopez at 12:06 PM | Permalink | Comments (3)

Have you had a chance to read our News Feature on the link between vaccination and autism? I encourage you to read it.

When we first discussed the idea of running this story, I didn't think there was much in it. After all, the main articles claiming the existence of such a link had been debunked some time ago. What was news to me, though, was how violent the parents of kids with autism have become. This is quite reminiscent of the strategy that animal activists have taken in the UK to make their point.

In the past, we have written editorials on how important it is for researchers to communicate science to the public, trying to help them distinguish between good and bad science. But cases like this make me wonder: would starting a serious dialogue with the concerned parents really make a difference? I sincerely doubt it. Once your emotional reactions take control of your intellect, arguments aren't likely to make any difference to your point of view.

Being the father of a child with a serious genetic disorder, I have had the opportunity to meet parents of similar kids and see in person how strongly their emotions can cloud their objectivity, particularly at the beginning of their ordeal, when they first get the news that their son or daughter is ill.

There is, however, a clear difference between these parents and the parents of kids with autism; whereas people like me cannot really channel our frustration against anyone other than our own genes, the parents of autistic kids have an easy target in advocates of vaccination schemes to protect kids from diseases that have been eradicated and in scientists who have worked to debunk the vaccine-autism link.

This irony makes their violence even more meaningless than that of animal activists.

Posted by Juan Carlos Lopez at 12:39 PM | Permalink | Comments (4)

The Stanley Medical Research Institute, a Maryland-based philanthropy, is donating $100 million to uncover the genes important in mental illnesses such as bipolar disorder and schizophrenia, according to an article in today's Boston Globe.

The money is going to the Broad Institute, led by genome bigwig Eric Lander, who was one of the driving forces behind the cancer genome. I've already noted the criticisms against that project, and some of the same apply here. Sure, technology now allows us to find the genetic variations between different people and the researchers will no doubt find masses of data.

But these are extremely complex disorders, each involving multiple genes. What roles do those genes play in the disease? Without understanding how the different genes interact and what the impact is of the different variations, the data will be all but meaningless. For example, scientists from the cancer genome project are reporting in this week's Nature that the number of mutations that drive cancer is much larger than they expected.

To the institute's credit, the mental illness project's results will be publicly available — the more scientists who can analyze the data the better. Lander is quoted in the Globe as saying, "If you're looking for a needle in a haystack, and you can sift the whole haystack, you'll find the needle."

Hmmm.... I don't think that was the message of the idiom.

Posted by Apoorva Mandavilli at 03:40 PM | Permalink | Comments (3)