Is Depression Undertreated?

Neuroskeptic readers will be familiar with the idea that too many people are being treated for mental illness. But not everyone agrees. Many people argue that common mental illnesses, such as depression, are undertreated. Take, for example, a paper just out in the esteemed Archives of General Psychiatry: Depression Care in the United States: Too Little for Too Few.

The authors looked at the results of three large (total N=15,762) surveys designed to measure the prevalence of mental illness in American adults. I've described how these surveys are conducted before: they took a randomly selected representative sample of Americans, and asked them a standardized series of questions (the CIDI interview) about their mood and emotions, in order to try to diagnose mental illness. The interviewers, while trained, were not clinicians.

What did they find? The rate of people experiencing Major Depressive Disorder (MDD), as defined in DSM-IV, in the past year, was 8.3%. When they examined ethnicity, this ranged from 6.7% in African Americans to 11.8% in Puerto Ricans. The average severity of the depression was roughly the same in all ethnic groups.

Of those with MDD, 51% reported that they'd had treatment in the past year, either antidepressants, psychotherapy, or both. This ranged from 53% for Whites down to just 29% of Caribbean Blacks and 33% of Mexican Americans. Therapy was somewhat more popular than drugs in all ethnic groups, although a lot of people used both. However, few of the treatments were classed as "guideline-concordant", i.e. long enough to do any good, which they defined as

use of an antidepressant for at least 60 days with supervision by a psychiatrist, or other prescribing clinician, for at least 4 visits in the past year. For psychotherapy...having at least 4 visits to a mental health professional in the past year lasting on average for at least 30 minutes each.
Only 21% of depressed people were getting such treatment, even though these strike me as very lenient guidelines, especially in the case of psychotherapy - how much good is 2 hours per year doing to do?


So depression's undertreated, especially in minorities. Too little, for too few. But this rests on an assumption: that we should treat Major Depressive Disorder.

That might not seem like an assumption, but assumptions generally don't. It seems like common sense, almost a tautology - it's a disorder, of course we should treat it! Yet it's not so simple. DSM-IV criteria for MDD require you to have 5 or more out of a list of 9 symptoms, including either depressed mood or a loss of interest in activities, lasting at least 2 weeks, and causing significant distress or impairment in social, occupational, or other important areas of functioning.

Fair enough. That's quite useful as a way of ensuring that psychiatrists in different countries are talking about the same thing when they talk about depression. But to think that depression is undertreated because only half of people meeting DSM-IV criteria for Major Depressive Disorder are being treated, is to put absolute faith in DSM-IV as a guide to who to treat. This is not what the DSM was meant to be, and there's no evidence it works for that purpose.

Is it really true that people with 5 symptoms need help, and those with 4 don't? Why not 6, or all 9? Why 2 weeks - why not 3 weeks, or 3 months? It's not as if there are loads of studies showing that treating people who have 5 symptoms for 2 weeks, and not treating people who don't, is the best strategy. I'm not aware of any such research. In particular, there's no evidence that people from the general population who meet these criteria when interviewed, but don't seek treatment, would all benefit from treatment as opposed to being left alone. Certainly some would, but they may be a minority.

This is not to say that any other criteria would be better than DSM-IV as guides to treatment, or that there is anything identifiably wrong with the DSM-IV criteria (although there is evidence that antidepressants are not useful in people with relatively "mild" MDD). The point is that doctors don't strictly apply textbook criteria when diagnosing and treating mental illness; they also use clinical judgement.

I don't know any psychiatrist who would prescribe treatment for someone solely on the basis that they met DSM-IV criteria for MDD. They would also want to know about the severity of the symptoms, whether they're related to any stresses or life events, how far they're "out of character" for that individual, etc. In general, they would deploy their training and experience to try to judge whether this person would benefit from treatment. This is why the DSM-IV carries a cautionary statement that "The proper use of these criteria requires specialized clinical training that provides both a body of knowledge and clinical skills."

So, it's far from clear that we should be treating everyone who answers interview questions in such a way that they meet DSM-IV criteria for Major Depressive Disorder. That's an assumption.

This isn't to say that everyone who needs depression treatment gets it. Sadly, there are many sufferers who would benefit from help and don't get any, or don't get it as early as they should. We need to do more to help such people. In this respect, depression is undertreated, although it's hard to know the extent of the problem. Yet it's quite possible that depression is also overtreated at the same time.

H/T Thanks to The Neurocritic for drawing my attention to this paper.

ResearchBlogging.orgGonzalez, H., Vega, W., Williams, D., Tarraf, W., West, B., & Neighbors, H. (2010). Depression Care in the United States: Too Little for Too Few Archives of General Psychiatry, 67 (1), 37-46 DOI: 10.1001/archgenpsychiatry.2009.168

A "Severe" Warning for Psychiatry

Imagine there was a nasty disease that affected 1 in 100 people. And imagine that someone invented a drug which treated it reasonably well. Good work, surely.

Now imagine that, for some reason, people decided that 10% of the population need to be taking this drug, instead of 1%. So sales of the drug sky-rocket. Eventually some clever person comes along and asks "This is one of the biggest selling drugs in the world - but does it work?" They look into it, and find that it doesn't work very well at all. For about 9 out of 10 people, it's completely useless! What a crap drug.

Of course the drug hasn't changed, and what's crap was the decision to prescribe it to so many people.


Back to reality. According to accepted DSM-IV diagnostic criteria, close to 50% of people suffer from a mental illness at some point; a large fraction of this being depression. 10% of Americans took antidepressants last year according to the best estimates.

Guess what? Clever people have started asking "Antidepressants are amongst the biggest selling drugs in the world - but do they work?" And their answer is - not very well. The latest such claim came from Fournier et al and appeared in JAMA a couple of weeks ago: Antidepressant Drug Effects and Depression Severity.

These researchers re-analysed the data from six clinical trials testing antidepressants against placebo pills. The drugs were the tricyclic imipramine and the newer SSRI paroxetine. The total sample size was a respectable 718, and most trials lasted 8 weeks, which is longer than average for this kind of study. Here's what they found -

Grey circles are people on antidepressants, white circles people on placebo. What this shows is that the more severe the patient's depression, the more they get better - when they're given either drugs or placebos. However, because the improvement on antidepressants rises more steeply, the benefit of antidepressants versus placebos correlates with severity. The thin blue line marks the minimum severity for which the average effect of the drugs over placebo was "clinically significant" according to NICE criteria (although these are arbitrary).


So, this study says that antidepressants work better in more severe depression. This is not a new claim - Kirsch et al (2008) famously found the same thing, and long before that so did Khan et al (2002). However this new analysis has some advantages over previous ones. First, Fournier et al looked at what happened to each patient individually, whereas the previous studies found that in trials where the patients were more severely depressed, on average, antidepressants worked better.

Second, the patients in this analysis spanned a wide range of severity scores, from 10 points on the Hamilton Scale to nearly 40. In Kirsch et al almost all the trials had average severities in the narrow range of 22 to 29. Finally, none of the trials in the new paper used a placebo run-in period. These are meant to exclude people from the trial if they improve "too well" during an initial week or so of placebo pills. In theory, they bias trials against finding large placebo effects; it's not clear they actually work, but either way, it's good to know it wasn't a factor.


Overall, the evidence all seems to point to the idea that people with more serious clinical depression respond better to antidepressants vs. placebos in clinical trials. The exact details are debatable, there's the issue of whether antidepressant clinical trials are realistic, and the question of how clinically effective antidepressants are is also controversial, but I'm not aware of any studies which have contradicted this central claim.

But when you start to think about it, this is a very odd result. Fournier et al say that
The general pattern of results reported in this work is not surprising. As early as the 1950s, researchers conducting controlled investigations of treatments for a wide variety of medical and psychiatric conditions described a phenomenon whereby patients with higher levels of severity showed greater differential (i.e., specific) benefit from the active treatments.
and refer to a couple of papers from the 1960s. But I must admit that I do find this very surprising. We don't wait until someone's nearly dead from a bacterial infection before we give them antibiotics, we give them early, when the disease is still mild. Doctors unfortunately don't tell people "Good news! You've got advanced-stage cancer - just the kind where drugs work best." Why is depression so different?

Look a little closer, and a possible answer emerges. Severity, in all of these studies, was measured using the Hamilton Rating Scale for Depression (HAMD). The HAMD has 17 items, and each asks whether you're suffering from certain symptoms; the more symptoms you have, and the more pronounced they are, the higher your total score. You get 1 point if you have "occasional difficulty falling asleep", 2 points for "nightly difficulty falling asleep", 4 points for "Hand wringing, nail biting, hair-pulling, biting of lips". Here's the whole thing.

The HAMD was designed in 1960 by a psychiatrist, Max Hamilton, and it was originally intended for use by staff at psychiatric hospitals for use on depressed inpatients. So it's not a measure of severity per se: it's a measure of how well your symptoms match those considered to be characteristic of severe depression in 1960.

Psychiatry's concept of depression - not to mention the wider culture's - has changed greatly since then. 1960 was a full 20 years before the DSM-III criteria of depression were published, which form the basis for today's DSM-IV criteria. A quick comparison of the DSM-IV alongside the HAMD reveals a lot of differences. It's quite possible to meet DSM-IV criteria for "Major Depressive Disorder" yet score low on the HAMD.

Which brings us back to the imaginary scenario at the start of this post. My personal interpretation of results like those of Fournier et al is this: antidepressants treat classical clinical depression, of the kind that psychiatrists in 1960 would have recognized. This is the kind of depression that they were originally used for, after all, because the first antidepressants arrived in 1953, and modern antidepressants like Prozac target the same neurotransmitter systems.

Yet in recent years "clinical depression" has become a much broader term. Many people attribute this to marketing on the part of pharmaceutical companies. Whatever the cause, it's almost certain that many people are now being prescribed antidepressants for emotional and personal issues which wouldn't have been considered medical illnesses until quite recently. (Antidepressants also have a long history of use for other conditions, like OCD, but this is a separate issue.)

My imaginary story used made up numbers: I'm not saying that only 10% of the people on antidepressants have "classic" depression. I don't know what the % is. But apart from that, in my opinion (and I don't think I'm alone), it's far from fantasy.

ResearchBlogging.orgFournier, J., DeRubeis, R., Hollon, S., Dimidjian, S., Amsterdam, J., Shelton, R., & Fawcett, J. (2010). Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis JAMA: The Journal of the American Medical Association, 303 (1), 47-53 DOI: 10.1001/jama.2009.1943

The Sweet Taste of Cannabinoids

Every stoner knows about the munchies, the fondness for junk food that comes with smoking marijuana. Movies have been made about it.

It's not just that being on drugs makes you like eating: stimulants, like cocaine and amphetamine, decrease appetite. The munchies are something specific to marijuana. But why?

New research from a Japanese team reveals that marijuana directly affects the cells in the taste buds which detect sweet flavours - Endocannabinoids selectively enhance sweet taste.

Yoshida et al studied mice, and recorded the electrical signals from the chorda tympani (CT), which carries taste information from the tongue to the brain.

They found that injecting the mice with two chemicals, 2AG and AEA, markedly increased the strength of the signals produced in response to sweet tastes - such as sugar, or the sweetener saccharine. However, neither had any effect on the strength of the response to other flavours, like salty, bitter, or sour. Mice given endocannabinoids were also more eager to eat and drink sweet things, which confirms previous findings.

2-AG and AEA are both endocannabinoids, an important class of neurotransmitters. Marijuana's main active ingredient, Δ9-THC, works by mimicking the action of endocannabinoids. Although Δ9-THC wasn't tested in this study, it's extremely likely that it has the same effects as 2-AG and AEA.

In follow-up experiments, Yoshida et al found that endocannabinoids enhance sweet taste responses by acting on cannabinoid type 1 (CB1) receptors on the tongue's sweet taste cells themselves. In fact, over half of the sweet receptor cells expressed CB1 receptors!

This is an important finding, because CB1 receptors are already known to regulate the pleasurable response to sweet foods (amongst other things) in the brain. These new data don't challenge this, but suggest that CB1 also modulates the most basic aspects of sweet taste perception. The munchies are probably caused by Δ9-THC acting at multiple levels of nervous system.

This paper also sheds light on CB1 antagonists. Given that drugs which activate CB1 make people eat more, it would make sense if CB1 blockers made people eat less, and therefore lose weight, a kind of anti-munchies effect. And indeed they do. Which is why rimonabant, a CB1 antagonist, was released onto the market in 2006 as a weight loss drug. It worked pretty well, although unfortunately it also it caused clinical depression in some people, so it was banned in Europe in 2008 and was never approved in the USA for the same reason.

The depression was almost certainly caused by antagonism at CB1 receptors in the brain, but Yoshida et al's findings suggest that a CB1 antagonist which didn't enter the brain, and only affected peripheral sites such as the taste buds, might be able to make people less fond of sweet foods without causing the same side-effects. Who knows - in a few years you might even be able to buy CB1 antagonist chewing gum to help you stick to your diet...

ResearchBlogging.orgYoshida, R., Ohkuri, T., Jyotaki, M., Yasuo, T., Horio, N., Yasumatsu, K., Sanematsu, K., Shigemura, N., Yamamoto, T., Margolskee, R., & Ninomiya, Y. (2009). Endocannabinoids selectively enhance sweet taste Proceedings of the National Academy of Sciences, 107 (2), 935-939 DOI: 10.1073/pnas.0912048107

A Brief History of Bipolar Kids

Can children get bipolar disorder?

It depends who you ask. It's "controversial". Some say that, like schizophrenia, bipolar strikes in adolescence or after, and that pre-pubertal onset is extraordinarily rare. Others say that kids can be, and often are, bipolar, but their symptoms may differ from the ones seen in adults. You know a 20 year old's manic when they stay up for 3 days straight writing a book about how God's chosen them to save the world. A "bipolar" 10 year old, though, is more likely to show irritability and mood swings. Critics say that this isn't evidence of bipolar, it's evidence of... irritability and mood swings. Or, indeed, of being 10.

But what's not always appreciated is how new the concept of pediatric bipolar as a common disorder is, and how specific it is to American psychiatry. Here are a few graphs I put together to illustrate this, based on numbers of scientific publications.

First up, when did people start talking about it? Here's the number of PubMed hits for pediatric bipolar each year. As you can see, it was rarely talked about before the year 2000, after which its popularity shot up rapidly; it seems to have plateaued now, but it's hard to tell.

In fact, the true trend is even more dramatic, because many of the early hits were not about psychiatry at all. For example, in 1999, 5 of the 10 were nothing to do with manic-depression. One was about the growth pattern of a certain kind of bacteria (they're "bipolar", because they have two poles of growth.)

Is the post-2000 spike just a reflection of the fact that people are publishing more papers about bipolar in general? No. Here's a graph showing pediatric bipolar hits as a fraction of all "bipolar disorder" hits for that year. It's been rising for a while and it's now 5%.

Where are these publications coming from? America. Taking the first two pages of PubMed hits for pediatric bipolar, and excluding the non-psychiatric ones, 30 are from the USA, and just 4 are from elsewhere. For "bipolar disorder", it's 13 vs. 25. (This is in terms of the affiliation listed for the primary authors of the study.)

What about paediatric bipolar, the British spelling? It's almost unheard of. There are only 53 PubMed hits in total, as against 564 for pediatric bipolar. Of the first 20 hits, 9 are non-psychiatric, and 3 are from an Australian journal, criticizing the American concept of pediatric bipolar!

It's remarkable that the monthly British Journal of Psychiatry has never published a paper about "pediatric bipolar" or "paediatric bipolar": if you search their archives you get just 5 hits, and they are all in the references sections, not the papers themselves. The monthly American Journal of Psychiatry has published 37 papers mentioning "pediatric bipolar", of which 25 are not just in the references, and 10 are in the titles.

So, at least in terms of the literature, pediatric bipolar is overwhelmingly a 21st century American phenomenon. It barely existed before 2000, and it barely exists elsewhere. This corresponds to what some non-American psychiatrists have observed. In The Paediatric Bipolar Hypothesis: The View from Australia and New Zealand, Australian psychiatrists Peter Parry, Gareth Furber and Stephen Allison point out that

Traditionally, bipolar affective disorder has been considered rare in children and uncommon in adolescence ... However paediatric bipolar disorder (PBD) has become a topical issue in child and adolescent psychiatry over the last decade, driven by research in the USA. The proponents of PBD are concerned that the traditional approach to bipolar disorder in children and adolescents is missing a large number of distressed children, whose course of bipolar illness could be ameliorated or attenuated by early treatment.
Pediatric bipolar has certainly become more common as a diagnosis in the USA recently - a 40-fold increase in 12 years up to 2003:
The number of visits to primary care physicians in the under 20 age group where the diagnosis was bipolar disorder increased from 0.01% in 1994/5 to 0.44% in 2002/3
Whereas elsewhere, it's still regarded as incredibly uncommon...
Soutullo et al. reported that none of the 2,500 children 10 years or younger referred to the Royal Manchester Children's Hospital ... had a diagnosis of mania or bipolar disorder ... A more recent German survey revealed German child and adolescent psychiatrists were largely holding to a traditional stance as only 8% claimed to have diagnosed a pre-pubertal child with bipolar disorder.
Parry, Furber and Allison then present the results of a survey of 199 child and adolescent psychiatrists in Australia and New Zealand.
The majority of participants (53.4%) said they had never seen a case of pre-pubertal bipolar disorder, whilst a further 28.5% estimated they'd seen only 1 or 2 cases. Only 35 participants (18.2%) estimated having seen 3 or more cases of pre-pubertal bipolar disorder. ... Most participants (83.1%) were of the opinion that bipolar disorder in pre-pubertal children was either "very rare (less than 0.01%)", "rare (less than 0.1%)", or "cannot be diagnosed in this age group".
Of course this is just a survey, but the results are striking.

Peter Parry reports as a conflict-of-interest that he's a member of Healthy Skepticism, who are, in their own words, in the business of "Improving health by reducing harm from misleading drug promotion". I'm sure neither he nor I need to spell out why drug companies might conceivably have an interest in promoting the concept of pediatric bipolar disorder, given the wide range of drugs available for bipolar adults...

ResearchBlogging.orgParry, P., Furber, G., & Allison, S. (2009). The Paediatric Bipolar Hypothesis: The View from Australia and New Zealand Child and Adolescent Mental Health, 14 (3), 140-147 DOI: 10.1111/j.1475-3588.2008.00505.x

A Decade for Psychiatric Disorders...?

Nature kicks off the 2010s with an editorial pep-talk for psychiatry: A decade for psychiatric disorders.

New techniques — genome-wide association studies, imaging and the optical manipulation of neural circuits — are ushering in an era in which the neural circuitry underlying cognitive dysfunctions, for example, will be delineated... Whether for schizophrenia, depression, autism or any other psychiatric disorders, it is clear... that understanding of these conditions is entering a scientific phase more penetratingly insightful than has hitherto been possible.
But I don't feel too peppy.

The 2010s is not the decade for psychiatric disorders. Clinically, that decade was the 1950s. The 50s was when the first generation of psychiatric drugs were discovered - neuroleptics for psychosis (1952), MAOis (1952) and tricyclics (1957) for depression, and lithium for mania (1949, although it took a while to catch on).

Since then, there have been plenty of new drugs invented, but not a single one has proven more effective than those available in 1959. New antidepressants like Prozac are safer in overdose, and have milder side effects, than older ones. New "atypical" antipsychotics have different side effects to older ones. But they work no better. Compared to lithium, newer "mood stabilizers" probably aren't even as good. (The only exception is clozapine, a powerful antipsychotic, but dangerous side-effects limit its use.)

Scientifically, the 1960s were the decade of psychiatry. We learned that antipsychotics block dopamine receptors in the brain, and that antidepressants inhibit the reuptake or breakdown of monoamines: noradrenaline and serotonin. So it was natural, if unimaginative, to hypothesise that psychosis is caused by "too much dopamine", and that depression is a case of "not enough monoamines". (As for lithium, we still don't know how it works. Two out of three ain't bad.)

These are still the core dogmas of biological psychiatry. Since the 60s, the amount of money and people involved in the field has exploded, but today's research is still essentially making footnotes to the work done 30 or 40 years ago. It would be somewhat unfair to say that we haven't made any solid advances since then, but only somewhat.

The double helix structure of DNA was discovered in 1953, just after antipsychotics and antidepressants. Imagine if biologists had learned about the double helix, but instead of using it to understand genetics, or catch criminals, or sequence genomes, they spent 50 years arguing about whether all DNA was shaped like that, or only some of it.

The standard response to the charge that psychiatry has lagged behind the rest of medicine is that "It's hard". And it is, because it's about human life, which is complex. But so is the subject matter of every science: the whole point is to seek simplicity in the complexity. Genetics was hard, until we worked out how to do it.

What's remarkable is that so many things in psychiatry are simple. For example: any drug which blocks the dopamine transporter (DAT) in the brain has stimulant effects: increased energy, focus, and motivation, and at high doses, euphoria, grandiosity, and potentially addiction. Cocaine, amphetamine, Ritalin etc all work this way. There are no cocaine-like drugs that don't block DAT and no DAT inhibitors that aren't cocaine-like. Simple. The stimulant high looks strikingly like the mania seen in bipolar disorder, and is pretty much the exact opposite of what happens in clinical depression. Couldn't be easier.

There are plenty of cases just like this. What's also striking is that neuroscience has advanced in leaps and bounds since the 1960s. A 60s, or even a 90s, textbook about neuroscience looks incredibly dated - a 60s psychiatry textbook is essentially still up-to-date except for the drug names. Contemporary neuroscience is far from being a mature science like genetics, it has its problems (see: all my previous posts) but compared to psychiatry, "basic" neuroscience is rock-solid. Although I trained as basic neuroscientist, so I would say that.

Why? That's an excellent question. But if you ask me, and judging by the academic literature I'm not alone, the answer is: diagnosis. The weak link in psychiatry research is the diagnoses we are forced to use: "major depressive disorder", "schizophrenia", etc.

Basic neuroscientists don't use these. If a neuroscientist wants to study the effect of, say, pepperoni pizza on the human caudate nucleus, they can order a Dominos, recruit their friends as research subjects, pop them in an MRI scanner and get to work doing rigorous (and delicious) science. They've got the pepperoni pizza, they've got the human caudate nucleus - away they go.

Whereas in order to do research in psychiatry, you need patients, and to decide who's a patient and who isn't you basically have to use DSM-IV criteria, which are all but meaningless in most cases. It doesn't matter what amazing new scientific tools you have - genome-wide association studies, proteomics, brain imaging, whatever. If you're using them to study differences between "depressed people" and "normal people", and your "depressed people" are a mix of people who aren't ill and just need a holiday or a divorce, undiagnosed thyroid cases, local bums lying about being depressed to get paid for being in the study, and (if you're lucky) a few "really" clinically depressed people, you'll not get very far.

Edit 10.1.2009 - Changed the date of the discovery of the structure of DNA from 1952 to the correct 1953, oops.

ResearchBlogging.orgNature (2010). A decade for psychiatric disorders Nature, 463 (7277), 9-9 DOI: 10.1038/463009a

Chronic Fatigue Syndrome in "not caused by single virus" shock!

Late last year, Science published a bombshell - Lombardi et al's Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. This paper reported the presence of a recently-discovered virus in 67% of the blood samples from 101 people with chronic fatigue syndrome (CFS).

The question of whether people with CFS are suffering from an organic illness, or whether their condition is partially or entirely psychological in nature, is the Israel vs. Palestine of modern medicine - as a brief look at the Wikipedia talk pages will show. So when Lombardi et al linked CFS to xenotropic murine leukaemia virus-related virus (XMRV), they were hailed as heroes by some, less so by others. For some balanced coverage of this paper, see virology blog. Everyone agreed though that Lombardi et al was, as the saying goes, "important if true"...

But it wasn't, at least not everywhere, according to a paper out today in PLoS ONE: Erlwein et al's Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome. The findings are all there in the title - unlike Lombardi et al, these researchers didn't find XMRV in the blood of any of their blood samples from 186 CFS patients.

Still, before people start proclaiming that the original finding has been "debunked", or decrying these results as flawed, some things to bear in mind...

This was a different country. Erlwein et al used patients attending the CFS clinic at King’s College Hospital, London, England. The patients in the original study were drawn from various parts of the USA. So the new results don't mean that the original findings were wrong, merely that they don't apply everywhere. Notably, XMRV has previously been detected in prostrate cancer cells from American patients, but not European ones, so geographic differences seem to be at work. So maybe XMRV does cause CFS, it's just that the virus doesn't exist in Europe, for whatever reason - but bear in mind that even the original study never showed causation, only a correlation. There are many viruses that infect people in certain parts of the world and don't cause illness.

On the other hand, it was a similar group of patients in terms of symptoms: Diagnosing CFS can be difficult, as there are no biological tests to confirm the condition, but Erlwein et al say that

Both studies use the widely accepted 1994 clinical case definition of CFS. Lombardi et al. reported that their cases ‘‘presented with severe disability’’ and we provide quantifiable evidence confirming high levels of disability in our subjects. Our subjects were also typical of those seen in secondary and tertiary care in other centres.
But the first study selected patients with "immunological abnormalities", although we're given few details...
These are patients that have been seen in private medical practices, and their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to perturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assays), and elevated cytokines particularly interleukin-6 and interleukin-8.
The biological methods were similar: Both studies used a standard technique called nested PCR. (Lombardi et al also used various other methods, but their headline finding of XMRV in 67% of CFS patients vs just 4% of health people came from nested PCR.) PCR is a way of greatly increasing the amount of a certain sequence of DNA in a sample. If there's even a little bit to start with, you end up with lots. If there's none, you end up with none. It's easy to tell the difference between lots and none.

But there were some differences. The first study only looked at a certain kind of white blood cells, whereas the new study used DNA from whole blood. Also, the first study targeted a larger span of viral DNA - from 419 to 1154:
For identification of gag, 419F and 1154R were used as forward and reverse primers.
Than the second one, which examined the section between positions 411 and 606. As a result, primer sequences used - which determine the DNA detected - were different. However, the authors of the new study claim that they would definitely have detected XMRV DNA if it had been there, because they used the same methods on control samples with the virus added, and got positive results...
The positive control was a dilution of a plasmid with a full-length XMRV (isolate VP62) insert, generously gifted by Dr R. Silverman.
Silverman was one of the authors of the original paper - so hopefully, both research teams were studying the same virus. But (although I'm no virologist) it seems possible that the new study might have been unable to detect XMRV if the DNA sequence of the virus from British patients was differed at certain key ways - the whole point about nested PCR is that it's extremely specific.

Finally, there are stories behind these papers. The first study, that suggested that XMRV causes CFS, was conducted by the Whittemore Peterson Institute, who firmly believe that CFS is an organic disorder and who are now offering XMRV diagnostic tests to CFS patients. By contrast, the authors of the new study include Simon Wessely, a psychiatrist. Wessely is the most famous (or notorious) advocate of the idea that psychological factors are the key to CFS; he believes that it should be treated with psychotherapy.

I'm sure we'll be hearing a lot more about XMRV in the coming months, so stay tuned.

ResearchBlogging.orgErlwein, O., Kaye, S., McClure, M., Weber, J., Wills, G., Collier, D., Wessely, S., & Cleare, A. (2010). Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008519

Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, & Mikovits JA (2009). Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science (New York, N.Y.), 326 (5952), 585-9 PMID: 19815723

The Neuroscience of MySpace

How does popularity affect how we judge music?

We tend to say we like what other people like. No-one wants to stand out and risk ridicule by saying they don't enjoy universally loved bands, like The Beatles... unless they're trying to fit into a subculture where everyone hates The Beatles.

But do people just pretend to like what others like, or can perceived popularity actually change musical preferences? Do The Beatles actually sound better because we know everyone loves them? An amusing Neuroimage study from Berns et al aimed to answer this question with the help of 27 American teens, an fMRI scanner, and MySpace.

The teens were played 15 second clips of music, and had to rate each one a 5 star scale of quality. Before the experiment they listed their preferred musical genres, and they were only given music from genres they liked. To make sure no-one had heard the songs before, the researchers went on MySpace and found unsigned artists...

A total of 20 songs were downloaded in each of the following genres: Rock, Country, Alternative/Emo/Indie, Hip-Hop/Rap, Jazz/Blues, and Metal (identified by the MySpace category).
The twist was that each song was played twice: the first time with no information about its popularity, and then again, either with or without a 5 star popularity score shown on the screen. Cleverly, this was based on the number of MySpace downloads. This meant that the subjects had a chance to change their rating based on what they'd just learned about the song's popularity.

What happened? Compared to doing nothing, hearing music activated large chunks of the brain, which is not very surprising. In some areas, activity correlated with how highly the listener rated the song:
The regions showing activity correlated with likability were largely distinct from the auditory network and were restricted to bilateral caudate nuclei, and right lateral prefrontal cortices (middle and inferior gyri). Negative correlations with likability were observed in bilateral supramarginal gyri, left insula, and several small frontal regions.
The headline result is that a song's popularity did not correlate with activity in this "liking music network", and nor did activity in these areas correlate with each teen's individual "conformism" score, i.e. how willing they were to change their ratings in response to learning about the song's popularity. Berns et al interpreted this as meaning that, in this experiment, popularity did not affect whether the volunteers really enjoyed the songs or not.

Instead, activity in some other areas was associated with conformism:
we found a positive interaction in bilateral anterior insula, ACC/SMA, and frontal poles. Given the known roles of the anterior insula and ACC in the cortical pain matrix, this suggests that feelings of anxiety accompanied the act of conforming....Interestingly, the negative interaction revealed significant differences in the middle temporal gyrus... the popularity sensitive individuals showed significantly less activation. This suggests that sensitivity to popularity is also linked to less active listening.


This paper is a good example of using neuroimaging data to try to test psychological theories, in this case, the theory that social pressure influences musical enjoyment. This is makes it better than many fMRI studies because, as I have warned, without a theory to test it's all too easy to just make up a psychological story to explain any given pattern of neural responses.

But there's still an element of this here: the authors suggest that conformism is motivated by anxiety, not because anyone reported suffering anxiety, but purely because it was associated with activity in the anterior insula etc. This is putting a lot of faith in the idea that anterior insula etc activity means anxiety - it could mean a lot of other things. There's also the question of whether letting people rate the songs for the first time before telling them about the popularity is the best way of measuring social pressures.

The most serious omission in this study, however, is that we're not told about the correlations between music preference and conformism. The world needs to know: are kids who like "Alternative/Emo/Indie" music free-thinkers, or are they really the biggest conformists of all? The paper doesn't tell us. In the absence of empirical evidence, we'll have to rely on South Park...
Stan: But if life is only pain, then...what's the point of living?
Fringe-flicking Goth: Just to make life more miserable for the conformists. (flicks fringe)
Stan: Alright, so how do I join you?
Goth Leader: If you wanna be one of the non-conformists, all you have to do is dress just like us and listen to the same music we do.
- South Park, "Raisins"

ResearchBlogging.orgBerns, G., Capra, C., Moore, S., & Noussair, C. (2010). Neural mechanisms of the influence of popularity on adolescent ratings of music NeuroImage, 49 (3), 2687-2696 DOI: 10.1016/j.neuroimage.2009.10.070

"Cortical Stimulation" for Depression

The last decade saw a number of new experimental treatments for depression based around the idea of using electricity to alter brain function - deep brain stimulation (DBS), vagus nerve stimulation (VNS), and transcranial magnetic stimulation (TMS).

The mechanics of these technologies differ, but they're all being promoted as options for "treatment-resistant depression" - depression which hasn't responded to more conventional approaches. They're also alike in that their usefulness is uncertain - either because there have been no randomized-controlled trials (DBS), or because the results of randomized trials are mixed at best (TMS,VNS).

Now there's a new kid on the neurostimulatory block: epidural prefrontal cortical stimulation (EpCS). This involves implanting electrodes beneath the skull, but above the meninges, the "skin" surrounding the brain. So it's unlike deep brain stimulation (DBS), in which the electrodes are placed inside the brain itself.

Late last year, Nahas et al reported on EpCS in a paper, Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression. They took 5 severely depressed patients, with either major depression or bipolar disorder, who'd all tried many treatments and experienced no benefit:

The mean age was 44.2 years. Four were women, and three were diagnosed with recurrent major depressive disorder; two others had bipolar affective disorder I, depressed type. All were unemployed, and three were receiving disability. The average length of depressive illness was 25.6 years. The average length of the current depressive episode was 3 years, 7 months ... participants had received an average of 9.8 unsuccessful clinical treatments during the current major depressive episode ... They enrolled in the study taking on average 6 psychotropic drugs.
Electrodes were implanted bilaterally over the "anterior and midlateral frontal cortex". This is as sensible a place to stimulate as any, although we really don't know what these parts of the brain do, or how they relate to depression. Nor do we know what "60 Hz, 2–4 V, 30 min on/ 2.5 hours off from 8 AM to 10 PM." stimulation does to these areas.

2 weeks after surgery the electricity was turned on, and the stimulation was then optimized over 2-3 weeks. Did it work? Out of the 5 patients, one didn't get any better, two felt somewhat better, and two were greatly improved at the end of the study 7 months post-op. And there were no major side effects or cognitive changes; one patient got a bacterial infection, but it was treatable. Hurrah!

But hang on. There was no control group, so the improvement could have been due to the placebo effect or, more likely, the passage of time. The guy with the single best response, Subject 2, was as depressed as ever during the first 4 months, but then improved dramatically by month 7. It may not be a coincidence that this subject was bipolar. Bipolar people who are depressed eventually stop being depressed - that's kind of the point.

Indeed, all of the others who improved did so between 2 weeks and 4 months after the stimulation was started, not straight away. So it's not like flicking a switch and turning off the depression... but on the other hand it's exactly that if you listen to what the patients say during the operation itself.

They reported feeling happier and less anxious as soon as the current was turned on (they weren't told when this was, so this is unlikely to have been a placebo effect). Some said things like
“I feel attentive,” “feel better and I can talk now,” “I can think clearer.” A patient noted during anterior frontal pole stimulation feeling as if a “weight [was] lifting off my shoulder,” “I feel calm”; another stated, “and although I am worried, I feel
dissociated from it. I can think back at my worry.”
Subject 2, the guy who got much better a long time after the operation, was the only patient who didn't enjoy any nice effects during the operation itself, which only adds to my suspicions that he would have got better anyway.

What does all this mean? It's hard to say. The results are very similar to those seen with DBS for depression - patients report suddenly feeling happier as soon as the current is turned on during the operation (the only placebo-controlled aspect of the trials), but afterwards the improvement seems gradual, taking weeks or months.

There's two main ways of interpreting this. The optimistic view is that stimulating the right bits of the brain instantly treats depression, and the apparent "time lag" in improvement after the operation is a product of the fact that when someone's been depressed for so long, as these patients have, it takes time for them to readjust to normal life even once they start feeling much better.

The pessimistic view is that stimulating the brain doesn't treat depression, it just causes a "high" which doesn't last very long, and the subsequent slow, gradual improvement would have happened anyway.

This is why we need randomized controlled trials. Nahas et al note that there has been one randomized controlled trial of EpCS for depression, comparing active EpCS to placebo EpCS with the electrodes switched off. It hasn't been published yet, but a preliminary analysis found no difference between the two conditions - it didn't work. And that trial was more than twice as big as this one (12 patients vs. 5). But, they point out, in that trial only the left side of the brain was stimulated, whereas they stimulated both sides.

Overall, just like DBS, EpCS could be either a great leap forward or a waste of time, money and neurosurgery. Hopefully, by the end of this decade, we'll know. Watch this space.

Links: Dr Shock covered this paper when it came out.

ResearchBlogging.orgNahas, Z., Anderson, B., Borckardt, J., Arana, A., George, M., Reeves, S., & Takacs, I. (2010). Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression Biological Psychiatry, 67 (2), 101-109 DOI: 10.1016/j.biopsych.2009.08.021

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