A Ghostwriter Speaks

PLoS ONE offers the confessions of a former medical ghostwriter: Being the Ghost in the Machine.





The article (which is open access and short, so well worth a read) explains how Linda Logdberg became a medical writer; what excited her about the job; what she actually did; and what made her eventually give it up.



Ghostwriting of course has a bad press at the moment and it's recently been banned by some leading research centres. Ghostwriting certainly is concerning, because of what it implies about the process leading up the publication.



However, it doesn't create bad science. A bad paper is bad because of what it says, not because of who (ghost)wrote it. Real scientists can write bad papers without a ghostwriter's help.



When pharmaceutical companies pay a ghostwriter, they are not doing this to get access to special dark arts that real scientists are innocent of. As far as I can see, it's just more efficient to use a specialist writer to do your scientific sins, when you're doing it all the time.



Rather like every evil sorcerer has an apprentice to do the day-to-day work of sacrificing animals and mixing potions.



Logdberg says:

My career came to an end over a job involving revising a manuscript supporting the use of a drug for attention deficit-hyperactivity disorder (ADHD), with a duration of action that fell between that of shorter- and longer-acting formulations.



However, I have two children with ADHD, and I failed to see the benefit of a drug that would wear off right at suppertime, rather than a few hours before or a few hours after. Suppertime is a time in ADHD households when tempers and homework arguments are often at their worst.



...Attempts to discuss my misgivings with the [medical] contact met with the curt admonition to ‘‘just write it.’’ But perhaps because this particular disorder was so close to home, I was unwilling to turn this ugly duckling of a ‘‘me-too’’ drug into a marketable swan.

Many scientists will recall being in that kind of situation, albeit in a different context.



When writing a grant application, for example, you are almost literally trying to sell your proposed research to the awarding committee, on several levels. You need to sell the importance of the scientific question; the likely practical benefits of the research; the chance of success using your methods; what makes you the right person to do this work, and so on.



Writing a paper is much the same, although in this case you're selling research you've already done, and the data you collected.



Turning ugly ducklings into fundable, or publishable, swans, is part and parcel of modern science. Of course, the ducklings are not always as ugly as in the case Logdberg describes, but they are rarely as beautiful as they eventually end up.



Logdberg, L. (2011). Being the Ghost in the Machine: A Medical Ghostwriter's Personal View PLoS Medicine, 8 (8) DOI: 10.1371/journal.pmed.1001071

A Ghostwriter Speaks

PLoS ONE offers the confessions of a former medical ghostwriter: Being the Ghost in the Machine.





The article (which is open access and short, so well worth a read) explains how Linda Logdberg became a medical writer; what excited her about the job; what she actually did; and what made her eventually give it up.



Ghostwriting of course has a bad press at the moment and it's recently been banned by some leading research centres. Ghostwriting certainly is concerning, because of what it implies about the process leading up the publication.



However, it doesn't create bad science. A bad paper is bad because of what it says, not because of who (ghost)wrote it. Real scientists can write bad papers without a ghostwriter's help.



When pharmaceutical companies pay a ghostwriter, they are not doing this to get access to special dark arts that real scientists are innocent of. As far as I can see, it's just more efficient to use a specialist writer to do your scientific sins, when you're doing it all the time.



Rather like every evil sorcerer has an apprentice to do the day-to-day work of sacrificing animals and mixing potions.



Logdberg says:

My career came to an end over a job involving revising a manuscript supporting the use of a drug for attention deficit-hyperactivity disorder (ADHD), with a duration of action that fell between that of shorter- and longer-acting formulations.



However, I have two children with ADHD, and I failed to see the benefit of a drug that would wear off right at suppertime, rather than a few hours before or a few hours after. Suppertime is a time in ADHD households when tempers and homework arguments are often at their worst.



...Attempts to discuss my misgivings with the [medical] contact met with the curt admonition to ‘‘just write it.’’ But perhaps because this particular disorder was so close to home, I was unwilling to turn this ugly duckling of a ‘‘me-too’’ drug into a marketable swan.

Many scientists will recall being in that kind of situation, albeit in a different context.



When writing a grant application, for example, you are almost literally trying to sell your proposed research to the awarding committee, on several levels. You need to sell the importance of the scientific question; the likely practical benefits of the research; the chance of success using your methods; what makes you the right person to do this work, and so on.



Writing a paper is much the same, although in this case you're selling research you've already done, and the data you collected.



Turning ugly ducklings into fundable, or publishable, swans, is part and parcel of modern science. Of course, the ducklings are not always as ugly as in the case Logdberg describes, but they are rarely as beautiful as they eventually end up.



Logdberg, L. (2011). Being the Ghost in the Machine: A Medical Ghostwriter's Personal View PLoS Medicine, 8 (8) DOI: 10.1371/journal.pmed.1001071

Brain-Modifying Drugs

What if there was a drug that didn't just affect the levels of chemicals in your brain, it turned off genes in your brain? That possibility - either exciting or sinister depending on how you look at it - could be remarkably close, according to a report just out from a Spanish group.

The authors took an antidepressant, sertraline, and chemically welded it to a small interfering RNA (siRNA). A siRNA is kind of like a pair of genetic handcuffs. It selectively blocks the expression of a particular gene, by binding to and interfering with RNA messengers. In this case, the target was the serotonin 5HT1A receptor.

The authors injected their molecule into the brains of some mice. The sertraline was there to target the siRNA at specific cell types. Sertraline works by binding to and blocking the serotonin transporter (SERT), and this is only expressed on cells that release serotonin; so only these cells were subject to the 5HT1A silencing.

The idea is that this receptor acts as a kind of automatic off-switch for these cells, making them reduce their firing in response to their own output, to keep them from firing too fast. There's a theory that this feedback can be a bad thing, because it stops antidepressants from being able to boost serotonin levels very much, although this is debated.

Anyway, it worked. The treated mice showed a strong and selective reduction in the density of the 5HT1A receptor in the target area (the Raphe nuclei containing serotonin cells), but not in the rest of the brain.

Note that this isn't genetic modification as such. The gene wasn't deleted, it was just silenced, temporarily one hopes; the effect persisted for at least 3 days, but they didn't investigate just how long it lasted.

That's remarkable enough, but what's more, it also worked when they administered the drug via the intranasal route. In many siRNA experiments, the payload is injected directly into the brain. That's fine for lab mice, but not very practical for humans. Intranasal administration, however, is popular and easy.

So siRNA-sertraline, and who knows what other drugs built along these lines, may be closer to being ready for human consumption than anyone would have predicted. However... the mouse's brain is a lot closer to its nose than the human brain is, so it might not go quite as smoothly.

The mind boggles at the potential. If you could selectively alter the gene expression of selective neurons, you could do things to the brain that are currently impossible. Existing drugs hit the whole brain, yet there are many reasons why you'd prefer to only affect certain areas. And editing gene expression would allow much more detailed control over those cells than is currently possible.

Currently available drugs are shotguns and sledgehammers. These approaches could provide sniper rifles and scalpels. But whether it will prove to be safe remains to be seen. I certainly wouldn't want to be first one to snort this particular drug.

Bortolozzi, A., Castañé, A., Semakova, J., Santana, N., Alvarado, G., Cortés, R., Ferrés-Coy, A., Fernández, G., Carmona, M., Toth, M., Perales, J., Montefeltro, A., & Artigas, F. (2011). Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects Molecular Psychiatry DOI: 10.1038/mp.2011.92

Brain-Modifying Drugs

What if there was a drug that didn't just affect the levels of chemicals in your brain, it turned off genes in your brain? That possibility - either exciting or sinister depending on how you look at it - could be remarkably close, according to a report just out from a Spanish group.

The authors took an antidepressant, sertraline, and chemically welded it to a small interfering RNA (siRNA). A siRNA is kind of like a pair of genetic handcuffs. It selectively blocks the expression of a particular gene, by binding to and interfering with RNA messengers. In this case, the target was the serotonin 5HT1A receptor.

The authors injected their molecule into the brains of some mice. The sertraline was there to target the siRNA at specific cell types. Sertraline works by binding to and blocking the serotonin transporter (SERT), and this is only expressed on cells that release serotonin; so only these cells were subject to the 5HT1A silencing.

The idea is that this receptor acts as a kind of automatic off-switch for these cells, making them reduce their firing in response to their own output, to keep them from firing too fast. There's a theory that this feedback can be a bad thing, because it stops antidepressants from being able to boost serotonin levels very much, although this is debated.

Anyway, it worked. The treated mice showed a strong and selective reduction in the density of the 5HT1A receptor in the target area (the Raphe nuclei containing serotonin cells), but not in the rest of the brain.

Note that this isn't genetic modification as such. The gene wasn't deleted, it was just silenced, temporarily one hopes; the effect persisted for at least 3 days, but they didn't investigate just how long it lasted.

That's remarkable enough, but what's more, it also worked when they administered the drug via the intranasal route. In many siRNA experiments, the payload is injected directly into the brain. That's fine for lab mice, but not very practical for humans. Intranasal administration, however, is popular and easy.

So siRNA-sertraline, and who knows what other drugs built along these lines, may be closer to being ready for human consumption than anyone would have predicted. However... the mouse's brain is a lot closer to its nose than the human brain is, so it might not go quite as smoothly.

The mind boggles at the potential. If you could selectively alter the gene expression of selective neurons, you could do things to the brain that are currently impossible. Existing drugs hit the whole brain, yet there are many reasons why you'd prefer to only affect certain areas. And editing gene expression would allow much more detailed control over those cells than is currently possible.

Currently available drugs are shotguns and sledgehammers. These approaches could provide sniper rifles and scalpels. But whether it will prove to be safe remains to be seen. I certainly wouldn't want to be first one to snort this particular drug.

Bortolozzi, A., Castañé, A., Semakova, J., Santana, N., Alvarado, G., Cortés, R., Ferrés-Coy, A., Fernández, G., Carmona, M., Toth, M., Perales, J., Montefeltro, A., & Artigas, F. (2011). Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects Molecular Psychiatry DOI: 10.1038/mp.2011.92

Antipsychotics - The New Valium?

Antipsychotics, originally designed to control the hallucinations and delusions seen in schizophrenia, have been expanding their domain in recent years.

Nowadays, they're widely used in bipolar disorder, depression, and as a new paper reveals, increasingly in anxiety disorders as well.

The authors, Comer et al, looked at the NAMCS survey, which provides yearly data on the use of medications in visits to office-based doctors across the USA.

Back in 1996, just 10% of visits in which an anxiety disorder was diagnosed ended in a prescription for an antipsychotic. By 2007 it was over 20%. No atypical is licensed for use in anxiety disorders in the USA, so all of these prescriptions are off-label.

Not all of these prescriptions will have been for anxiety. They may have been prescribed to treat psychosis, in people who also happened to be anxious. However, the increase was accounted for by the rise in non-psychotic patients, and there was a rise in the rate of people with only anxiety disorders.

The increase was driven by the newer, "atypical" antipsychotics.

Whether the modern trend for prescribing antipsychotics for anxiety is a good or a bad thing, is not for us to say. The authors discuss various concerns ranging from the side effects (obesity, diabetes and more), to the fact that there have only been a few clinical trials of these drugs in anxiety.

But what's really disturbing about these results, to me, is how fast the change happened. Between 2000 and 2004, use doubled from 10% to 20% of anxiety visits. That's an astonishingly fast change in medical practice.

Why? It wasn't because that period saw the publication of a load of large, well-designed clinical trials demonstrating that these drugs work wonders in anxiety disorders. It didn't.

But as Comer et al put it:

An increasing number of office-based psychiatrists are specializing in pharmacotherapy to the exclusion of psychotherapy. Limitations in the availability of psychosocial interventions may place heavy clinical demands on the pharmacological dimensions of mental health care for anxiety disorder patients.

In other words, antipsychotics may have become popular because they're the treatment for people who can't afford anything better.

These data show that antipsychotics were over twice as likely to be prescribed to African American patients; the poor i.e. patients with public health insurance; and children under 18.

Comer JS, Mojtabai R, & Olfson M (2011). National Trends in the Antipsychotic Treatment of Psychiatric Outpatients With Anxiety Disorders. The American journal of psychiatry PMID: 21799067

Antipsychotics - The New Valium?

Antipsychotics, originally designed to control the hallucinations and delusions seen in schizophrenia, have been expanding their domain in recent years.

Nowadays, they're widely used in bipolar disorder, depression, and as a new paper reveals, increasingly in anxiety disorders as well.

The authors, Comer et al, looked at the NAMCS survey, which provides yearly data on the use of medications in visits to office-based doctors across the USA.

Back in 1996, just 10% of visits in which an anxiety disorder was diagnosed ended in a prescription for an antipsychotic. By 2007 it was over 20%. No atypical is licensed for use in anxiety disorders in the USA, so all of these prescriptions are off-label.

Not all of these prescriptions will have been for anxiety. They may have been prescribed to treat psychosis, in people who also happened to be anxious. However, the increase was accounted for by the rise in non-psychotic patients, and there was a rise in the rate of people with only anxiety disorders.

The increase was driven by the newer, "atypical" antipsychotics.

Whether the modern trend for prescribing antipsychotics for anxiety is a good or a bad thing, is not for us to say. The authors discuss various concerns ranging from the side effects (obesity, diabetes and more), to the fact that there have only been a few clinical trials of these drugs in anxiety.

But what's really disturbing about these results, to me, is how fast the change happened. Between 2000 and 2004, use doubled from 10% to 20% of anxiety visits. That's an astonishingly fast change in medical practice.

Why? It wasn't because that period saw the publication of a load of large, well-designed clinical trials demonstrating that these drugs work wonders in anxiety disorders. It didn't.

But as Comer et al put it:

An increasing number of office-based psychiatrists are specializing in pharmacotherapy to the exclusion of psychotherapy. Limitations in the availability of psychosocial interventions may place heavy clinical demands on the pharmacological dimensions of mental health care for anxiety disorder patients.

In other words, antipsychotics may have become popular because they're the treatment for people who can't afford anything better.

These data show that antipsychotics were over twice as likely to be prescribed to African American patients; the poor i.e. patients with public health insurance; and children under 18.

Comer JS, Mojtabai R, & Olfson M (2011). National Trends in the Antipsychotic Treatment of Psychiatric Outpatients With Anxiety Disorders. The American journal of psychiatry PMID: 21799067

New Antidepressant - Old Tricks

The past decade has been a bad one for antidepressant manufacturers.

Quite apart from all the bad press these drugs have been getting lately, there's been a remarkable lack of new antidepressants making it to the market. The only really novel drugs to hit the shelves since 2000 have been agomelatine and vilazodone. There were a couple of others that were just minor variants on old molecules, but that's it. Quite a contrast from the 1990s when new drugs were ten-a-penny.

This makes "Lu AA21004" rather special. It's a new antidepressant currently in development and by all accounts it's making good progress. It's now in Phase III trials, the last stage before approval. And a large clinical trial has just been published finding that it works.

But is it a medical advance or merely a commercial one?

Pharmacologically, Lu AA21004 is kind of a new twist on an old classic . Its main mechanism of action is inhibiting the reuptake of serotonin, just like Prozac and other SSRIs. However, unlike them, it also blocks serotonin 5HT3 and 5HT7 receptors, activates 5HT1A receptors and partially agonizes 5HT1B.

None of these things cry out "antidepressant" to me, but they do at least make it a bit different.

The new trial took 430 depressed people and randomized them to get Lu AA21004, at two different doses, 5mg or 10mg, or the older antidepressant venlafaxine at the high-ish dose of 225 mg, or placebo.

It worked. Over 6 weeks, people on the new drug improved more than those on placebo, and equally as well as people on venlafaxine; the lower 5 mg dose was a bit less effective, but not significantly so.

The size of the effect was medium, with a benefit over-and-above placebo of about 5 points on the MADRS depression scale, which considering that the baseline scores in this study averaged 34, is not huge, but it compares well to other antidepressant trials.

Now we come to the side effects, and this is the most important bit, as we'll see later. The authors did not specifically probe for these, they just relied on spontaneous report, which tends to underestimate adverse events.


Basically, the main problem with Lu AA21004 was that it made people sick. Literally - 9% of people on the highest dose suffered vomiting, and 38% got nausea. However, the 5 mg dose was no worse than venlafaxine for nausea, and was relatively vomit-free. Unlike venlafaxine, it didn't cause dry mouth, constipation, or sexual problems.

So that's lovely then. Let's get this stuff to market!

Hang on.

The big selling point for this drug is clearly the lack of side effects. It was no more effective than the (much cheaper, because off-patent) venlafaxine. It was better tolerated, but that's not a great achievement to be honest. Venlafaxine is quite notorious for causing side effects, especially at higher doses.

I take venlafaxine 300 mg and the side effects aren't the end of the world, but they're no fun, and the point is, they're well known to be worse than you get with other modern drugs, most notably SSRIs.

If you ask me, this study should have compared the new drug to an SSRI, because they're used much more widely than venlafaxine. Which one? How about escitalopram, a drug which is, according to most of the literature, one of the best SSRIs, as effective as venlafaxine, but with fewer side effects.

Actually, according to Lundbeck, who make escitalopram, it's even better than venlafaxine. Now, they would say that, given that they make it - but the makers of Lu AA21004 ought to believe them, because, er, they're the same people. "Lu" stands for Lundbeck.

The real competitor for this drug, according to Lundbeck, is escitalopram. But no-one wants to be in competition with themselves.

This may be why, although there are no fewer than 26 registered clinical trials of Lu AA21004 either ongoing or completed, only one is comparing it to an SSRI. The others either compare it to venlafaxine, or to duloxetine, which has even worse side effects. The one trial that will compare it to escitalopram has a narrow focus (sexual dysfunction).

Pharmacologically, remember, this drug is an SSRI with a few "special moves", in terms of hitting some serotonin receptors. The question is - do those extra tricks actually make it better? Or is it just a glorified, and expensive, new SSRI? We don't know and we're not going to find out any time soon.

If Lu AA21004 is no more effective, and no better tolerated, than tried-and-tested old escitalopram, anyone who buys it will be paying extra for no real benefit. The only winner, in that case, being Lundbeck - especially given that escitalopram goes off-patent in 2012...

Alvarez E, Perez V, Dragheim M, Loft H, & Artigas F (2011). A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. The International Journal of Neuropsychopharmacology , 1-12 PMID: 21767441

New Antidepressant - Old Tricks

The past decade has been a bad one for antidepressant manufacturers.

Quite apart from all the bad press these drugs have been getting lately, there's been a remarkable lack of new antidepressants making it to the market. The only really novel drugs to hit the shelves since 2000 have been agomelatine and vilazodone. There were a couple of others that were just minor variants on old molecules, but that's it. Quite a contrast from the 1990s when new drugs were ten-a-penny.

This makes "Lu AA21004" rather special. It's a new antidepressant currently in development and by all accounts it's making good progress. It's now in Phase III trials, the last stage before approval. And a large clinical trial has just been published finding that it works.

But is it a medical advance or merely a commercial one?

Pharmacologically, Lu AA21004 is kind of a new twist on an old classic . Its main mechanism of action is inhibiting the reuptake of serotonin, just like Prozac and other SSRIs. However, unlike them, it also blocks serotonin 5HT3 and 5HT7 receptors, activates 5HT1A receptors and partially agonizes 5HT1B.

None of these things cry out "antidepressant" to me, but they do at least make it a bit different.

The new trial took 430 depressed people and randomized them to get Lu AA21004, at two different doses, 5mg or 10mg, or the older antidepressant venlafaxine at the high-ish dose of 225 mg, or placebo.

It worked. Over 6 weeks, people on the new drug improved more than those on placebo, and equally as well as people on venlafaxine; the lower 5 mg dose was a bit less effective, but not significantly so.

The size of the effect was medium, with a benefit over-and-above placebo of about 5 points on the MADRS depression scale, which considering that the baseline scores in this study averaged 34, is not huge, but it compares well to other antidepressant trials.

Now we come to the side effects, and this is the most important bit, as we'll see later. The authors did not specifically probe for these, they just relied on spontaneous report, which tends to underestimate adverse events.


Basically, the main problem with Lu AA21004 was that it made people sick. Literally - 9% of people on the highest dose suffered vomiting, and 38% got nausea. However, the 5 mg dose was no worse than venlafaxine for nausea, and was relatively vomit-free. Unlike venlafaxine, it didn't cause dry mouth, constipation, or sexual problems.

So that's lovely then. Let's get this stuff to market!

Hang on.

The big selling point for this drug is clearly the lack of side effects. It was no more effective than the (much cheaper, because off-patent) venlafaxine. It was better tolerated, but that's not a great achievement to be honest. Venlafaxine is quite notorious for causing side effects, especially at higher doses.

I take venlafaxine 300 mg and the side effects aren't the end of the world, but they're no fun, and the point is, they're well known to be worse than you get with other modern drugs, most notably SSRIs.

If you ask me, this study should have compared the new drug to an SSRI, because they're used much more widely than venlafaxine. Which one? How about escitalopram, a drug which is, according to most of the literature, one of the best SSRIs, as effective as venlafaxine, but with fewer side effects.

Actually, according to Lundbeck, who make escitalopram, it's even better than venlafaxine. Now, they would say that, given that they make it - but the makers of Lu AA21004 ought to believe them, because, er, they're the same people. "Lu" stands for Lundbeck.

The real competitor for this drug, according to Lundbeck, is escitalopram. But no-one wants to be in competition with themselves.

This may be why, although there are no fewer than 26 registered clinical trials of Lu AA21004 either ongoing or completed, only one is comparing it to an SSRI. The others either compare it to venlafaxine, or to duloxetine, which has even worse side effects. The one trial that will compare it to escitalopram has a narrow focus (sexual dysfunction).

Pharmacologically, remember, this drug is an SSRI with a few "special moves", in terms of hitting some serotonin receptors. The question is - do those extra tricks actually make it better? Or is it just a glorified, and expensive, new SSRI? We don't know and we're not going to find out any time soon.

If Lu AA21004 is no more effective, and no better tolerated, than tried-and-tested old escitalopram, anyone who buys it will be paying extra for no real benefit. The only winner, in that case, being Lundbeck - especially given that escitalopram goes off-patent in 2012...

Alvarez E, Perez V, Dragheim M, Loft H, & Artigas F (2011). A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. The International Journal of Neuropsychopharmacology , 1-12 PMID: 21767441

The Brain Is Not Made Of Soup

A critical article about psychiatry has been doing the rounds. Regular Neuroskeptic readers will be all too familiar with the issues here, but to many people they're news.

Here's an article summarizing the original piece. The author's the head of a British think tank, but not a specialist in mental health, so he's probably a good example of the ''intelligent layman":

Neither – in relation to the fastest rising [mental health] diagnoses – is there any evidence of chemical imbalances in the brains of patients. In other words, the problem the [psychiatric] drugs are supposed to solve is an illusion.

There's no evidence of fairies in my garden, either. The concept of a 'chemical imbalance' in the human brain is one of the most fantastic oversimplifications in science, and one of the worst legacies of the modern pharmaceutical industry.

A bowl of soup could have a chemical imbalance. If you're making a chicken broth and you accidentally put in an extra spoonful of coriander, it'll taste horrible. Not enough salt, and it'll be bland. A soup is simple: too much or too little of one thing, and it comes out wrong.

Or...does it? Actually, flavour isn't just the sum of the ingredients. You might put in some extra coriander, and also put in some chilli powder, and that would end up delicious whereas if you left the coriander the same, it would be overwhelmed by the chilli. But you'll need to rethink the paprika as well...

Soups are pretty complicated.

The brain is a restaurant with a hundred billion tables. At each table sits a food critic. An army of chefs prepares an infinity of soups - no two are the same, although some areas of the restaurant tend to get certain kinds - and a legion of waiters serves them up, collects the old bowls and takes them to the kitchen to be washed and refilled.

Each critic has his own preferences. If she gets the right soup, she'll be happy. One soup will be great for one critic, disgusting to another. Some critics demand an ever-changing series of courses, others want the same thing day in day out.

Whether the restaurant gets a good review will depend on the composition of the soups, of course, but on so much else as well: are they delivered on time? Do the waiters collect the empty bowls quickly enough - or do they do it too fast, snatching soup away before it's been eaten? Who are the critics, anyhow?

This is still far too simple. In fact, the waiters and the chefs and the dishwashers are the critics, and how they do their job depends on what soup they're getting. That depends on how they've done their jobs in the past... and everyone's also a musician, playing their part in a symphony that we can't hear and couldn't begin to understand if we did.

Our technology for investigating the chemistry of the brain is comically crude. We can't even take a sample of all of the soups in the whole restaurant, mix them all up and measure their average ingredients. You can do that in animals, but for ethical reasons, not in humans. No-one has ever measured the chemical composition of a living human brain.

We can approximately measure a few very common ingredients. After death we can measure a few more. We can also do a kind of straw poll of critics to see what they like, but we don't know which particular critics answer it, or what soups they are in fact being served. Every month, someone discovers a whole new ingredient.

We can sneak into the kitchen and chuck some spice into the pots, to see what kind of noise the critics make. We can't hear what they're saying, we can only measure the volume from different parts of the restaurant. Some of the most informative studies come from measuring the composition of the waste that gets thrown out in the bins every night.

So next time someone confidently tells you that mental illness either is, or isn't, a chemical imbalance, ask them - which one?

The Brain Is Not Made Of Soup

A critical article about psychiatry has been doing the rounds. Regular Neuroskeptic readers will be all too familiar with the issues here, but to many people they're news.

Here's an article summarizing the original piece. The author's the head of a British think tank, but not a specialist in mental health, so he's probably a good example of the ''intelligent layman":

Neither – in relation to the fastest rising [mental health] diagnoses – is there any evidence of chemical imbalances in the brains of patients. In other words, the problem the [psychiatric] drugs are supposed to solve is an illusion.

There's no evidence of fairies in my garden, either. The concept of a 'chemical imbalance' in the human brain is one of the most fantastic oversimplifications in science, and one of the worst legacies of the modern pharmaceutical industry.

A bowl of soup could have a chemical imbalance. If you're making a chicken broth and you accidentally put in an extra spoonful of coriander, it'll taste horrible. Not enough salt, and it'll be bland. A soup is simple: too much or too little of one thing, and it comes out wrong.

Or...does it? Actually, flavour isn't just the sum of the ingredients. You might put in some extra coriander, and also put in some chilli powder, and that would end up delicious whereas if you left the coriander the same, it would be overwhelmed by the chilli. But you'll need to rethink the paprika as well...

Soups are pretty complicated.

The brain is a restaurant with a hundred billion tables. At each table sits a food critic. An army of chefs prepares an infinity of soups - no two are the same, although some areas of the restaurant tend to get certain kinds - and a legion of waiters serves them up, collects the old bowls and takes them to the kitchen to be washed and refilled.

Each critic has his own preferences. If she gets the right soup, she'll be happy. One soup will be great for one critic, disgusting to another. Some critics demand an ever-changing series of courses, others want the same thing day in day out.

Whether the restaurant gets a good review will depend on the composition of the soups, of course, but on so much else as well: are they delivered on time? Do the waiters collect the empty bowls quickly enough - or do they do it too fast, snatching soup away before it's been eaten? Who are the critics, anyhow?

This is still far too simple. In fact, the waiters and the chefs and the dishwashers are the critics, and how they do their job depends on what soup they're getting. That depends on how they've done their jobs in the past... and everyone's also a musician, playing their part in a symphony that we can't hear and couldn't begin to understand if we did.

Our technology for investigating the chemistry of the brain is comically crude. We can't even take a sample of all of the soups in the whole restaurant, mix them all up and measure their average ingredients. You can do that in animals, but for ethical reasons, not in humans. No-one has ever measured the chemical composition of a living human brain.

We can approximately measure a few very common ingredients. After death we can measure a few more. We can also do a kind of straw poll of critics to see what they like, but we don't know which particular critics answer it, or what soups they are in fact being served. Every month, someone discovers a whole new ingredient.

We can sneak into the kitchen and chuck some spice into the pots, to see what kind of noise the critics make. We can't hear what they're saying, we can only measure the volume from different parts of the restaurant. Some of the most informative studies come from measuring the composition of the waste that gets thrown out in the bins every night.

So next time someone confidently tells you that mental illness either is, or isn't, a chemical imbalance, ask them - which one?

Bipolar Kids: You Read It Here First

Last year, I discussed the controvery over the proposed new childhood syndrome of "Temper Disregulation Disorder with Dysphoria" (TDDD). It may be included in the upcoming revision of the psychiatric bible, DSM-V.

Back then, I said:

TDDD has been proposed in order to reduce the number of children being diagnosed with pediatric bipolar disorder... many people agree that pediatric bipolar is being over-diagnosed.

So we can all sympathize with the sentiment behind TDDD - but this is fighting fire with fire. Is the only way to stop kids getting one diagnosis, to give them another one? Should we really be creating diagnoses for more or less "strategic" purposes?

Now, a bunch of psychiatrists have written to the Journal of Clinical Psychiatry to express their concerns over the proposed diagnosis. They make the same point that I did:

We believe that the creation of a new, unsubstantiated diagnosis in order to prevent misapplication of a different diagnosis is misguided and a step backward for the progression of psychiatry as a rational scientific discipline.

Although they go into much more detail in critiquing the evidence held up in favor of the idea of TDDD. They also point out that it is rather optimistic to think, as some people apparantly do, that if we were to diagnose kids with TDDD, as opposed to childhood bipolar, we'd save them from getting nasty bipolar medications.

As they say, the risk is that drug companies would just get their drugs licensed to treat TDDD instead. Same drugs, different label. It would be fairly easy: just for starters, there are plenty of sedative drugs, such as atypical antipsychotics, which would certainly alter or mask the "symptoms" of TDDD, in the short term. Doing a clinical trial and showing that these drugs "work" would be easy. It wouldn't mean they actually worked, or that TDDD actually existed.

They also point out that the public perception of child psychiatry has already been harmed by the proposal of TDDD, and would suffer further if it were to become official.

Well, of course it would, and quite rightly so. That would be a sign that child psychiatry is so out of control that, literally, the only way it can stop diagnosing children, is to diagnose them with something else!

The same issue of the the same journal features another paper, claiming that "pediatric bipolar disorder" has a prevalence rate of 1.8%, and that rates of diagnosis of childhood bipolar are not higher in the USA than elsewhere, contrary to popular belief based on evidence.

Their data are a bunch of epidemiological studies on bipolar disorder. One of which included children up to the age of...21. The majority included kids of 17 or 18.

So, er, not children at all, then.


The older the "children" in the study, the more bipolar that study found. Everyone knows that bipolar disorder typically starts in late adolescence. That's the orthodoxy and it has been since Kraepelin. It's right there at the top of the Wikipedia page. That's not pediatric bipolar, that's just normal bipolar.

All the recent controversy is about bipolar in children. As in, like, 8 year olds. Yet this paper is still titled "Meta-analysis of epidemiologic studies of pediatric bipolar disorder". The senior author on this paper also signed the paper criticizing TDDD.

This, then, is the state of the debate over the future of our children.

P.S. I've just noticed that in the latest draft of DSM-V, TDDD has been renamed. It's now called "DMDD". What's next? DUDD? DEDD? P-DIDDY ?

Axelson DA, Birmaher B, Findling RL, Fristad MA, Kowatch RA, Youngstrom EA, Arnold EL, Goldstein BI, Goldstein TR, Chang KD, Delbello MP, Ryan ND, & Diler RS (2011). Concerns regarding the inclusion of temper dysregulation disorder with dysphoria in the DSM-V The Journal of clinical psychiatry PMID: 21672494

Van Meter AR, Moreira AL, & Youngstrom EA (2011). Meta-analysis of epidemiologic studies of pediatric bipolar disorder. The Journal of clinical psychiatry PMID: 21672501

Bipolar Kids: You Read It Here First

Last year, I discussed the controvery over the proposed new childhood syndrome of "Temper Disregulation Disorder with Dysphoria" (TDDD). It may be included in the upcoming revision of the psychiatric bible, DSM-V.

Back then, I said:

TDDD has been proposed in order to reduce the number of children being diagnosed with pediatric bipolar disorder... many people agree that pediatric bipolar is being over-diagnosed.

So we can all sympathize with the sentiment behind TDDD - but this is fighting fire with fire. Is the only way to stop kids getting one diagnosis, to give them another one? Should we really be creating diagnoses for more or less "strategic" purposes?

Now, a bunch of psychiatrists have written to the Journal of Clinical Psychiatry to express their concerns over the proposed diagnosis. They make the same point that I did:

We believe that the creation of a new, unsubstantiated diagnosis in order to prevent misapplication of a different diagnosis is misguided and a step backward for the progression of psychiatry as a rational scientific discipline.

Although they go into much more detail in critiquing the evidence held up in favor of the idea of TDDD. They also point out that it is rather optimistic to think, as some people apparantly do, that if we were to diagnose kids with TDDD, as opposed to childhood bipolar, we'd save them from getting nasty bipolar medications.

As they say, the risk is that drug companies would just get their drugs licensed to treat TDDD instead. Same drugs, different label. It would be fairly easy: just for starters, there are plenty of sedative drugs, such as atypical antipsychotics, which would certainly alter or mask the "symptoms" of TDDD, in the short term. Doing a clinical trial and showing that these drugs "work" would be easy. It wouldn't mean they actually worked, or that TDDD actually existed.

They also point out that the public perception of child psychiatry has already been harmed by the proposal of TDDD, and would suffer further if it were to become official.

Well, of course it would, and quite rightly so. That would be a sign that child psychiatry is so out of control that, literally, the only way it can stop diagnosing children, is to diagnose them with something else!

The same issue of the the same journal features another paper, claiming that "pediatric bipolar disorder" has a prevalence rate of 1.8%, and that rates of diagnosis of childhood bipolar are not higher in the USA than elsewhere, contrary to popular belief based on evidence.

Their data are a bunch of epidemiological studies on bipolar disorder. One of which included children up to the age of...21. The majority included kids of 17 or 18.

So, er, not children at all, then.


The older the "children" in the study, the more bipolar that study found. Everyone knows that bipolar disorder typically starts in late adolescence. That's the orthodoxy and it has been since Kraepelin. It's right there at the top of the Wikipedia page. That's not pediatric bipolar, that's just normal bipolar.

All the recent controversy is about bipolar in children. As in, like, 8 year olds. Yet this paper is still titled "Meta-analysis of epidemiologic studies of pediatric bipolar disorder". The senior author on this paper also signed the paper criticizing TDDD.

This, then, is the state of the debate over the future of our children.

P.S. I've just noticed that in the latest draft of DSM-V, TDDD has been renamed. It's now called "DMDD". What's next? DUDD? DEDD? P-DIDDY ?

Axelson DA, Birmaher B, Findling RL, Fristad MA, Kowatch RA, Youngstrom EA, Arnold EL, Goldstein BI, Goldstein TR, Chang KD, Delbello MP, Ryan ND, & Diler RS (2011). Concerns regarding the inclusion of temper dysregulation disorder with dysphoria in the DSM-V The Journal of clinical psychiatry PMID: 21672494

Van Meter AR, Moreira AL, & Youngstrom EA (2011). Meta-analysis of epidemiologic studies of pediatric bipolar disorder. The Journal of clinical psychiatry PMID: 21672501

Pharmaceuticals And Violence

A French study reveals which medications are most often associated with violence and aggression: Prescribed drugs and violence.


The authors trawled the French records of drug side effects from 1985 to 2008. By law, doctors in France must report any adverse event which is either serious, or unexpected, to the authorities.

They found a total of 540 reports mentioning "violence", but only 56 of these were clear-cut incidents of physical aggression towards others. Suicide and self-harm were not included, unless they also involved violence to other people.

There were 76 suspect drugs (because some reports included one or more). Here's the Hall of Shame:

16 reports involved benzodiazepines (Valium) or similar drugs.
13 implicated dopamine-boosting drugs used to treat Parkinson's disease.
4 were caused by serotonin-based antidepressants like Prozac. Older antidepressants were not associated.

Antipsychotics and anti-epileptics were also high on the list.

There were also reports involving and the antiviral drugs interferon (3), ribavarin(2), and efavirenz (3); the stop-smoking aid varenicline (4); anti-acne drug isotretinoin (4); and the banned weight-loss drug rimonabant (2). All of these can also cause depression, and I've blogged about some of them before for that reason.

Of the perpetrators, 86% were men. Nearly half had a prior psychiatric history, but that's not surprising because many of these drugs are prescribed to people with mental illness.

In terms of the number of reports of violence relative to the total number of adverse events for each drug, Parkinson's drugs were "worst". However, this doesn't mean much, because it might just mean that these drugs are generally mild in terms of side effects.

So it's an interesting dataset, but it's impossible to come to any firm conclusions as to how common these effects really are. Cases might go unreported if they're thought to be "normal" violence; and regular violence could also get wrongly blamed on a drug - criminals get sick too.

Finally, we ought to remember while these effects are inherently attention-grabbing (and Parkinson's drugs in particular have given rise to some tabloid-friendly stories), the overall rate was tiny - less than 3 cases per year, for all prescribed drugs, in a nation of over 60 million people.

Rouve N, Bagheri H, Telmon N, Pathak A, Franchitto N, Schmitt L, Rougé D, Lapeyre-Mestre M, Montastruc JL, & the French Association of Regional PharmacoVigilance Centres (2011). Prescribed drugs and violence: a case/noncase study in the French PharmacoVigilance Database. European journal of clinical pharmacology PMID: 21655992

Pharmaceuticals And Violence

A French study reveals which medications are most often associated with violence and aggression: Prescribed drugs and violence.


The authors trawled the French records of drug side effects from 1985 to 2008. By law, doctors in France must report any adverse event which is either serious, or unexpected, to the authorities.

They found a total of 540 reports mentioning "violence", but only 56 of these were clear-cut incidents of physical aggression towards others. Suicide and self-harm were not included, unless they also involved violence to other people.

There were 76 suspect drugs (because some reports included one or more). Here's the Hall of Shame:

16 reports involved benzodiazepines (Valium) or similar drugs.
13 implicated dopamine-boosting drugs used to treat Parkinson's disease.
4 were caused by serotonin-based antidepressants like Prozac. Older antidepressants were not associated.

Antipsychotics and anti-epileptics were also high on the list.

There were also reports involving and the antiviral drugs interferon (3), ribavarin(2), and efavirenz (3); the stop-smoking aid varenicline (4); anti-acne drug isotretinoin (4); and the banned weight-loss drug rimonabant (2). All of these can also cause depression, and I've blogged about some of them before for that reason.

Of the perpetrators, 86% were men. Nearly half had a prior psychiatric history, but that's not surprising because many of these drugs are prescribed to people with mental illness.

In terms of the number of reports of violence relative to the total number of adverse events for each drug, Parkinson's drugs were "worst". However, this doesn't mean much, because it might just mean that these drugs are generally mild in terms of side effects.

So it's an interesting dataset, but it's impossible to come to any firm conclusions as to how common these effects really are. Cases might go unreported if they're thought to be "normal" violence; and regular violence could also get wrongly blamed on a drug - criminals get sick too.

Finally, we ought to remember while these effects are inherently attention-grabbing (and Parkinson's drugs in particular have given rise to some tabloid-friendly stories), the overall rate was tiny - less than 3 cases per year, for all prescribed drugs, in a nation of over 60 million people.

Rouve N, Bagheri H, Telmon N, Pathak A, Franchitto N, Schmitt L, Rougé D, Lapeyre-Mestre M, Montastruc JL, & the French Association of Regional PharmacoVigilance Centres (2011). Prescribed drugs and violence: a case/noncase study in the French PharmacoVigilance Database. European journal of clinical pharmacology PMID: 21655992

Antivirals and Suicide

A case report from India describes a man who became suicidally depressed while being given drugs to treat a viral infection:

A 43-year-old man diagnosed with chronic hepatitis C viral infection ... was started on therapy with interferon -α-2a and ribavirin ... Screening tests for hepatitis B virus, hepatitis A virus, and HIV were negative.

In initial 3 months of start of therapy with IFN-α-2a and ribavirin, the patient experienced adverse effects in the form of high-grade fever, malaise, myalgia, and fatigue which were relieved by paracetamol. After 16 weeks of therapy, the patient reported to experience feeling of guilt, anxiety, fear, and sadness.

He wanted to keep himself isolated from family and friends. He started blaming himself for financial crises he was facing that time. He was unable to perform his job as school teacher. Hamilton Depression Rating Scale (HDRS-17) revealed the patient to be suffering from moderate to severe depression with score of 15.

He was given psychotherapy for the same. Paroxetine and zolpidem were started [but] he did not respond significantly to antidepressants over 3 weeks. After 25 days of starting antidepressants, the patient attempted suicide but was rescued in time.

IFN-α-2a and ribavirin were withheld for 1 month and antidepressants were continued. Patient's condition normalized and he started taking interest in self and surroundings. He started following his normal routine.

He was then put back on the drugs for 3 weeks, but he got depressed again. So treatment was aborted and he was back to feeling fine within a week.

Interferons are powerful antivirals but they have the dubious honor of being one of the few medical drugs clearly implicated in causing depression. Others include reserpine, an anti-hypertensive and rimonabant, a weight-loss drug (it got banned for this reason).

The anti-malarial mefloquine can cause a range of neuropsychiatric symptoms including depression but also hallucinations and nightmares, as can the HIV drug efavirenz which I covered recently.

Most people who take each of these drugs don't experience problems but in a non-trivial minority it happens. It obviously poses a serious problem for doctors, but it's also very interesting for people researching mood and depression. Work out why these drugs cause depression, and it might help work out why people get "normal" clinical depression.

For example, just recently it was shown that mefloquine has a unique and unusual effect on cells in the dopamine system of the brain, responsible for motivation and pleasure. Whether this explains the side-effects is an open question but without mefloquine we wouldn't even be able to ask it.

As for interferons, which are actually not drugs as such but rather molecules produced by the immune system during infections, it's given rise to the inflammation theory of depression. There's always a risk, though, that by focussing too much on just one class of depressing drug, you'll end up with a narrow theory that can't account for the others.

Inder D, Rehan HS, Yadav M, Manak S, & Kumar P (2011). IFN-α-2a (Interferon) and ribavirin induced suicidal attempt in a patient of chronic HCV: A rare case report. Indian journal of pharmacology, 43 (2), 210-1 PMID: 21572662

Antivirals and Suicide

A case report from India describes a man who became suicidally depressed while being given drugs to treat a viral infection:

A 43-year-old man diagnosed with chronic hepatitis C viral infection ... was started on therapy with interferon -α-2a and ribavirin ... Screening tests for hepatitis B virus, hepatitis A virus, and HIV were negative.

In initial 3 months of start of therapy with IFN-α-2a and ribavirin, the patient experienced adverse effects in the form of high-grade fever, malaise, myalgia, and fatigue which were relieved by paracetamol. After 16 weeks of therapy, the patient reported to experience feeling of guilt, anxiety, fear, and sadness.

He wanted to keep himself isolated from family and friends. He started blaming himself for financial crises he was facing that time. He was unable to perform his job as school teacher. Hamilton Depression Rating Scale (HDRS-17) revealed the patient to be suffering from moderate to severe depression with score of 15.

He was given psychotherapy for the same. Paroxetine and zolpidem were started [but] he did not respond significantly to antidepressants over 3 weeks. After 25 days of starting antidepressants, the patient attempted suicide but was rescued in time.

IFN-α-2a and ribavirin were withheld for 1 month and antidepressants were continued. Patient's condition normalized and he started taking interest in self and surroundings. He started following his normal routine.

He was then put back on the drugs for 3 weeks, but he got depressed again. So treatment was aborted and he was back to feeling fine within a week.

Interferons are powerful antivirals but they have the dubious honor of being one of the few medical drugs clearly implicated in causing depression. Others include reserpine, an anti-hypertensive and rimonabant, a weight-loss drug (it got banned for this reason).

The anti-malarial mefloquine can cause a range of neuropsychiatric symptoms including depression but also hallucinations and nightmares, as can the HIV drug efavirenz which I covered recently.

Most people who take each of these drugs don't experience problems but in a non-trivial minority it happens. It obviously poses a serious problem for doctors, but it's also very interesting for people researching mood and depression. Work out why these drugs cause depression, and it might help work out why people get "normal" clinical depression.

For example, just recently it was shown that mefloquine has a unique and unusual effect on cells in the dopamine system of the brain, responsible for motivation and pleasure. Whether this explains the side-effects is an open question but without mefloquine we wouldn't even be able to ask it.

As for interferons, which are actually not drugs as such but rather molecules produced by the immune system during infections, it's given rise to the inflammation theory of depression. There's always a risk, though, that by focussing too much on just one class of depressing drug, you'll end up with a narrow theory that can't account for the others.

Inder D, Rehan HS, Yadav M, Manak S, & Kumar P (2011). IFN-α-2a (Interferon) and ribavirin induced suicidal attempt in a patient of chronic HCV: A rare case report. Indian journal of pharmacology, 43 (2), 210-1 PMID: 21572662