Pharmaceutical Company Threatens Blogger

Boiron, a multinational pharmaceutical company, have threatened an Italian blogger with legal action, the BMJ reports.



Many people are concerned when big pharmaceutical companies do this kind of thing. So I don't think we should make any exception merely because Boiron's pharmaceuticals happen to be homeopathic ones.



Samuel Riva, who blogs (in Italian) at blogzero.it, put up some articles critical of homeopathy

which included pictures of Boiron’s blockbuster homoeopathic product Oscillococcinum, marketed as a remedy against flu symptoms. The pictures were accompanied by captions, which joked about the total absence of any active molecules in homoeopathic preparations

Boiron wrote to Riva's internet provider threatening legal action, if the offending references to Boiron weren't taken down. They also wanted them to lock Riva out of his blog, the BMJ says. In response Riva removed the references to Boiron, including the pictures and captions, but kept the posts on homeopathy in general.



Hmmm.



Above you can see a new picture I made of a Boiron product, with some captions you may find interesting. I've made sure to limit these to quotes from Wikipedia, and from Boiron USA's own website, and some simple mathematical calculations.



Beyond that, I make no comment whatsoever.



Turone F (2011). Homoeopathy multinational Boiron threatens amateur Italian blogger. BMJ (Clinical research ed.), 343 PMID: 21840920

Pharmaceutical Company Threatens Blogger

Boiron, a multinational pharmaceutical company, have threatened an Italian blogger with legal action, the BMJ reports.



Many people are concerned when big pharmaceutical companies do this kind of thing. So I don't think we should make any exception merely because Boiron's pharmaceuticals happen to be homeopathic ones.



Samuel Riva, who blogs (in Italian) at blogzero.it, put up some articles critical of homeopathy

which included pictures of Boiron’s blockbuster homoeopathic product Oscillococcinum, marketed as a remedy against flu symptoms. The pictures were accompanied by captions, which joked about the total absence of any active molecules in homoeopathic preparations

Boiron wrote to Riva's internet provider threatening legal action, if the offending references to Boiron weren't taken down. They also wanted them to lock Riva out of his blog, the BMJ says. In response Riva removed the references to Boiron, including the pictures and captions, but kept the posts on homeopathy in general.



Hmmm.



Above you can see a new picture I made of a Boiron product, with some captions you may find interesting. I've made sure to limit these to quotes from Wikipedia, and from Boiron USA's own website, and some simple mathematical calculations.



Beyond that, I make no comment whatsoever.



Turone F (2011). Homoeopathy multinational Boiron threatens amateur Italian blogger. BMJ (Clinical research ed.), 343 PMID: 21840920

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

Do We Need Placebos?

A news feature in Nature asks whether placebo controls are always a good idea: Why Fake It?



The piece looks at experimental neurosurgical treatments for Parkinson's, such as "Spheramine". This consists of cultured human cells, which are implanted directly into the brain of the sufferer. The idea is that the cells will grow and help produce dopamine, which is deficient in Parkinson's.



Peggy Willocks, a 44 year old teacher, took part in a trial of the surgery in 2000. She says it helped stave off the symptoms for years, but the development of Spheramine was axed in 2008 after a controlled trial found it didn't work any better than a placebo.



The placebo was "sham surgery" i.e. putting the patient through a full surgical procedure, and making holes in their skull, but without doing anything to their brain.



It's cheap and easy to do a placebo controlled trial of a drug - all you need is a sugar pill. But with neurosurgery, it's clearly a lot more involved. A placebo has to be believable. Convincing sham surgery is expensive, time-consuming, and it has real risks, albeit small ones.



Is it ethical to put patients through that?



That, I think, can only be decided on a trial-by-trial basis. It depends on the likely benefits of the treatment, and whether the trial is scientifically sound. Obviously, it'd be wrong to do sham surgery as part of a flawed trial that won't tell us anything useful.



The Nature article, however, goes further than this, and suggests that placebo controlled trials may be unsuitable for testing these kinds of treatments, failing to detect a real benefit in some patients:

There are hints from some of the failed phase II trials that patients followed up beyond study endpoints might tell a more positive story. Some say, therefore, that sham controls are sinking the prospects of valuable drugs.



Anders Björklund, a neuroscientist at Lund University in Sweden who is collaborating with [Roger Barker of Cambridge], says that sham surgery can lead researchers to throw out a strategy prematurely if the trial fails because of technical or methodological glitches rather than a true lack of efficacy.

A patient advocate agrees:

According to Perry Cohen, who leads a network of patient activists called the Parkinson Pipeline Project, that’s exactly what is happening. He had always questioned the need for sham surgery, he says, but after the string of phase II failures, “We started saying, ‘Hey, this is a problem. These trials failed, but we know they are working for some people.’”

...Cohen [says] that patients have different priorities and that researchers must take these into account. Researchers use placebo controls to weed out false positives. But for patients, the real ogre is the false negatives — which can sink a therapy before it has been optimized.

I'm not sure about this. If I had Parkinson's, I would certainly hate to miss out on the genuine cure because a trial had failed to recognize that it worked. But equally, I would not be happy to be given a rubbish treatment that would have failed a placebo controlled trial, but never got one, because of arguments like this.



Placebo controlled trials can fail to detect benefits if they are too short, too small, methodologically flawed, or whatever. Certainly, a trial can be placebo controlled, and still crap. But the answer is surely to do better trials, not no trials.



It may well be that we shouldn't rush to do placebo controlled trials until later in the development process, when the technique has been properly refined. But the history of medicine is littered with treatments that "we know work for some people" - that didn't.



Katsnelson, A. (2011). Experimental therapies for Parkinson's disease: Why fake it? Nature, 476 (7359), 142-144 DOI: 10.1038/476142a

Do We Need Placebos?

A news feature in Nature asks whether placebo controls are always a good idea: Why Fake It?



The piece looks at experimental neurosurgical treatments for Parkinson's, such as "Spheramine". This consists of cultured human cells, which are implanted directly into the brain of the sufferer. The idea is that the cells will grow and help produce dopamine, which is deficient in Parkinson's.



Peggy Willocks, a 44 year old teacher, took part in a trial of the surgery in 2000. She says it helped stave off the symptoms for years, but the development of Spheramine was axed in 2008 after a controlled trial found it didn't work any better than a placebo.



The placebo was "sham surgery" i.e. putting the patient through a full surgical procedure, and making holes in their skull, but without doing anything to their brain.



It's cheap and easy to do a placebo controlled trial of a drug - all you need is a sugar pill. But with neurosurgery, it's clearly a lot more involved. A placebo has to be believable. Convincing sham surgery is expensive, time-consuming, and it has real risks, albeit small ones.



Is it ethical to put patients through that?



That, I think, can only be decided on a trial-by-trial basis. It depends on the likely benefits of the treatment, and whether the trial is scientifically sound. Obviously, it'd be wrong to do sham surgery as part of a flawed trial that won't tell us anything useful.



The Nature article, however, goes further than this, and suggests that placebo controlled trials may be unsuitable for testing these kinds of treatments, failing to detect a real benefit in some patients:

There are hints from some of the failed phase II trials that patients followed up beyond study endpoints might tell a more positive story. Some say, therefore, that sham controls are sinking the prospects of valuable drugs.



Anders Björklund, a neuroscientist at Lund University in Sweden who is collaborating with [Roger Barker of Cambridge], says that sham surgery can lead researchers to throw out a strategy prematurely if the trial fails because of technical or methodological glitches rather than a true lack of efficacy.

A patient advocate agrees:

According to Perry Cohen, who leads a network of patient activists called the Parkinson Pipeline Project, that’s exactly what is happening. He had always questioned the need for sham surgery, he says, but after the string of phase II failures, “We started saying, ‘Hey, this is a problem. These trials failed, but we know they are working for some people.’”

...Cohen [says] that patients have different priorities and that researchers must take these into account. Researchers use placebo controls to weed out false positives. But for patients, the real ogre is the false negatives — which can sink a therapy before it has been optimized.

I'm not sure about this. If I had Parkinson's, I would certainly hate to miss out on the genuine cure because a trial had failed to recognize that it worked. But equally, I would not be happy to be given a rubbish treatment that would have failed a placebo controlled trial, but never got one, because of arguments like this.



Placebo controlled trials can fail to detect benefits if they are too short, too small, methodologically flawed, or whatever. Certainly, a trial can be placebo controlled, and still crap. But the answer is surely to do better trials, not no trials.



It may well be that we shouldn't rush to do placebo controlled trials until later in the development process, when the technique has been properly refined. But the history of medicine is littered with treatments that "we know work for some people" - that didn't.



Katsnelson, A. (2011). Experimental therapies for Parkinson's disease: Why fake it? Nature, 476 (7359), 142-144 DOI: 10.1038/476142a

So Apparantly I'm Bipolar

According to a new paper, yours truly is bipolar.





I've written before of my experience of depression, and the fact that I take antidepressants, but I've never been diagnosed with bipolar.



I've taken a few drugs in my time. On certain dopamine-based drugs I got euphoric, filled with energy, talkative, confident, with no need for sleep, and a boundless desire to do stuff, which is textbook hypomania. So I think I know what it feels like, and I can confidently say that it has never happened to me out of the blue.



On antidepressants, I have had some mild experiences of this type. Ironically, the closest I've come to it was when I quit an SSRI antidepressant. I've also experienced periods of irritability and agitation on antidepressants. Either way, that's antidepressants. Bipolar is when you get high on your own supply of neurotransmitters.



Well, it used to be. Jules Angst et al have got some new, broader criteria for "bipolarity" in depression. They say that manic symptoms in response to antidepressants do count, exactly like out-of-the-blue mania.



What's more, under the new "Bipolar Specifier" criteria, there's no minimum duration. Under existing criteria the symptoms have to last 4 or 7 days, depending on severity. Under the new regime if you've ever been irritable, high, agitated or hyperactive, on antidepressants or not, you meet "Bipolar Specifier" criteria, so long as it was marked enough that someone else noticed it.



All you need is:

an episode of elevated mood, an episode of irritable mood, or an episode of increased activity with at least 3 of the symptoms listed under Criterion B of the DSM-IV-TR associated with at least 1 of the 3 following consequences: (1) unequivocal and observable change in functioning uncharacteristic of the person’s usual behavior, (2) marked impairment in social or occupational functioning observable by others, or (3) requiring hospitalization or outpatient treatment.

The bipolar net just got bigger. And they caught me in it. Me and 47% of depressed people in their study. They recruited 509 psychiatrists from around the world, and got each of them to assess between 10 and 20 consecutive adult depressed patients who were referred to them for evaluation or treatment. A total of 5635 patients were included.



Only 16% met existing DSM-IV criteria for bipolar disorder, so the new system with 47% identified an "extra" 31%, trebling the number of bipolar cases.



A cynic would say that this is a breathtaking piece of psychiatric marketing. You give people antidepressants, then you diagnose them with bipolar on the basis of their reaction to those drugs, thus justifying selling them yet more drugs.



The cynic would not be surprised to learn that this study was sponsored by pharmaceutical company Sanofi.

All investigators recruited received fees, on a per patient basis, from sanofi-aventis in

recognition of their participation in the study....The sponsor of this study (sanofi-aventis) was involved in the study design, conduct, monitoring, data analysis, and preparation of the report.

In fairness, the authors do show that patients meeting their criteria tend to have characteristics typical of bipolar people. And they show that their system is at least as good as DSM-IV at picking out these cases:



For example, DSM-IV bipolar patients had a younger age of onset than DSM-IV depressed ones. "Bipolar specifier" patients did too, compared to the 53% who didn't meet the criteria. Same for a family history of manic symptoms, multiple episodes, and shorter episodes. All of those are pretty well established correlates of bipolar disorder.



That's fine, and the results are better than I expected when I picked up this paper. But all this shows us is that the bipolar specifier was no worse than the DSM-IV criteria as applied in this study.



It doesn't tell us whether either was any good.



DSM-IV criteria were used in a mechanical cookbook fashion - symptoms were assessed by the psychiatrist, written down, sent back to the study authors, who then diagnosed them if they ticked enough boxes. Is that a good approach? We don't know.



Most importantly, we have no idea whether these people would do better being treated as bipolar rather than as depressed. The difference being that bipolar people get mood stabilizers. Maybe these people would benefit from mood stabilizers, maybe not. Existing literature on mood stabilizers in bipolar people can't be assumed to generalize to these 47%.



In the discussion, the authors argue that antidepressants are not much good in bipolar people, whereas mood stabilizers are. Fun fact: Sanofi make many of the most popular formulations of valproic acid/valproate , a big selling mood stabilizer.



I think that is no coincidence. Maybe that sounds crazy, but hey, what do you expect? I'm bipolar.



Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Gamma A, Young AH, & for the BRIDGE Study Group (2011). Prevalence and Characteristics of Undiagnosed Bipolar Disorders in Patients With a Major Depressive Episode: The BRIDGE Study. Archives of general psychiatry, 68 (8), 791-798 PMID: 21810644

So Apparantly I'm Bipolar

According to a new paper, yours truly is bipolar.





I've written before of my experience of depression, and the fact that I take antidepressants, but I've never been diagnosed with bipolar.



I've taken a few drugs in my time. On certain dopamine-based drugs I got euphoric, filled with energy, talkative, confident, with no need for sleep, and a boundless desire to do stuff, which is textbook hypomania. So I think I know what it feels like, and I can confidently say that it has never happened to me out of the blue.



On antidepressants, I have had some mild experiences of this type. Ironically, the closest I've come to it was when I quit an SSRI antidepressant. I've also experienced periods of irritability and agitation on antidepressants. Either way, that's antidepressants. Bipolar is when you get high on your own supply of neurotransmitters.



Well, it used to be. Jules Angst et al have got some new, broader criteria for "bipolarity" in depression. They say that manic symptoms in response to antidepressants do count, exactly like out-of-the-blue mania.



What's more, under the new "Bipolar Specifier" criteria, there's no minimum duration. Under existing criteria the symptoms have to last 4 or 7 days, depending on severity. Under the new regime if you've ever been irritable, high, agitated or hyperactive, on antidepressants or not, you meet "Bipolar Specifier" criteria, so long as it was marked enough that someone else noticed it.



All you need is:

an episode of elevated mood, an episode of irritable mood, or an episode of increased activity with at least 3 of the symptoms listed under Criterion B of the DSM-IV-TR associated with at least 1 of the 3 following consequences: (1) unequivocal and observable change in functioning uncharacteristic of the person’s usual behavior, (2) marked impairment in social or occupational functioning observable by others, or (3) requiring hospitalization or outpatient treatment.

The bipolar net just got bigger. And they caught me in it. Me and 47% of depressed people in their study. They recruited 509 psychiatrists from around the world, and got each of them to assess between 10 and 20 consecutive adult depressed patients who were referred to them for evaluation or treatment. A total of 5635 patients were included.



Only 16% met existing DSM-IV criteria for bipolar disorder, so the new system with 47% identified an "extra" 31%, trebling the number of bipolar cases.



A cynic would say that this is a breathtaking piece of psychiatric marketing. You give people antidepressants, then you diagnose them with bipolar on the basis of their reaction to those drugs, thus justifying selling them yet more drugs.



The cynic would not be surprised to learn that this study was sponsored by pharmaceutical company Sanofi.

All investigators recruited received fees, on a per patient basis, from sanofi-aventis in

recognition of their participation in the study....The sponsor of this study (sanofi-aventis) was involved in the study design, conduct, monitoring, data analysis, and preparation of the report.

In fairness, the authors do show that patients meeting their criteria tend to have characteristics typical of bipolar people. And they show that their system is at least as good as DSM-IV at picking out these cases:



For example, DSM-IV bipolar patients had a younger age of onset than DSM-IV depressed ones. "Bipolar specifier" patients did too, compared to the 53% who didn't meet the criteria. Same for a family history of manic symptoms, multiple episodes, and shorter episodes. All of those are pretty well established correlates of bipolar disorder.



That's fine, and the results are better than I expected when I picked up this paper. But all this shows us is that the bipolar specifier was no worse than the DSM-IV criteria as applied in this study.



It doesn't tell us whether either was any good.



DSM-IV criteria were used in a mechanical cookbook fashion - symptoms were assessed by the psychiatrist, written down, sent back to the study authors, who then diagnosed them if they ticked enough boxes. Is that a good approach? We don't know.



Most importantly, we have no idea whether these people would do better being treated as bipolar rather than as depressed. The difference being that bipolar people get mood stabilizers. Maybe these people would benefit from mood stabilizers, maybe not. Existing literature on mood stabilizers in bipolar people can't be assumed to generalize to these 47%.



In the discussion, the authors argue that antidepressants are not much good in bipolar people, whereas mood stabilizers are. Fun fact: Sanofi make many of the most popular formulations of valproic acid/valproate , a big selling mood stabilizer.



I think that is no coincidence. Maybe that sounds crazy, but hey, what do you expect? I'm bipolar.



Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Gamma A, Young AH, & for the BRIDGE Study Group (2011). Prevalence and Characteristics of Undiagnosed Bipolar Disorders in Patients With a Major Depressive Episode: The BRIDGE Study. Archives of general psychiatry, 68 (8), 791-798 PMID: 21810644