Antidepressants In The UK

Antidepressant sales have been rising for many years in Western countries, as regular Neuroskeptic readers  will remember.

Most of the studies on antidepressant use come from the USA and the UK, although the pattern also seems to hold for other European countries. The rapid rise of antidepressants from niche drugs to mega-sellers is perhaps the single biggest change in the way medicine treats mental illness since the invention of psychiatric drugs.

But while a rise in sales has been observed in many countries, that doesn't mean the same causes were at work in every case. For example, in the USA, there is good evidence that more people have started taking antidepressants over the past 15 years.

In the UK, however, it's a bit more tricky. Antidepressant prescriptions have certainly risen. However, a large 2009 study revealed that, between 1993 and 2005, there was not any significant rise in people starting on antidepressants for depression. Rather, the rise in prescriptions was caused by patients getting more prescriptions each. The same number of users were using more antidepressants.

Now a new paper has looked at antidepressant use over much the same period (1995-2007), but using a different set of data. Pauline Lockhart and Bruce Guthrie looked at pharmacy records of drugs actually dispensed, not just prescribed, and their data only covers a specific region, Tayside in Scotland. The 2009 study was nationwide.

So what happened?

The new paper confirmed the 2009 survey's finding of a strong increase in the number of antidepressant prescriptions per patient.

However, unlike the old study, this one found an increase in the number of people who used antidepressants each year. It went up from 8% of the population in 1995, to 13% in 2007 - an extremely high figure, higher even than the USA.

In other words, more people took them, and they took more of them on average - adding up to a threefold increase in antidepressants actually sold. The increase was seen across men and women of all ages and social classes.

There's no good evidence of an increase in mental illness in Britain in this period, by the way.

But why did the 2009 paper report no change in antidepressant users, while this one did? It could be that the increase was localized to the Tayside area. Another possibility is that there was an increase nationwide, but it wasn't about people with depression.

The 2009 study only looked at people with a diagnosis of depression. Yet modern antidepressants are widely used for other things as well - like anxiety, insomnia, pain, premature ejaculation. Maybe this non-depression-based use of antidepressants is what's on the rise.

Lockhart, P. and Guthrie, B. (2011). Trends in primary care antidepressantprescribing 1995–2007 British Journal of General Practice

Antidepressants In The UK

Antidepressant sales have been rising for many years in Western countries, as regular Neuroskeptic readers  will remember.

Most of the studies on antidepressant use come from the USA and the UK, although the pattern also seems to hold for other European countries. The rapid rise of antidepressants from niche drugs to mega-sellers is perhaps the single biggest change in the way medicine treats mental illness since the invention of psychiatric drugs.

But while a rise in sales has been observed in many countries, that doesn't mean the same causes were at work in every case. For example, in the USA, there is good evidence that more people have started taking antidepressants over the past 15 years.

In the UK, however, it's a bit more tricky. Antidepressant prescriptions have certainly risen. However, a large 2009 study revealed that, between 1993 and 2005, there was not any significant rise in people starting on antidepressants for depression. Rather, the rise in prescriptions was caused by patients getting more prescriptions each. The same number of users were using more antidepressants.

Now a new paper has looked at antidepressant use over much the same period (1995-2007), but using a different set of data. Pauline Lockhart and Bruce Guthrie looked at pharmacy records of drugs actually dispensed, not just prescribed, and their data only covers a specific region, Tayside in Scotland. The 2009 study was nationwide.

So what happened?

The new paper confirmed the 2009 survey's finding of a strong increase in the number of antidepressant prescriptions per patient.

However, unlike the old study, this one found an increase in the number of people who used antidepressants each year. It went up from 8% of the population in 1995, to 13% in 2007 - an extremely high figure, higher even than the USA.

In other words, more people took them, and they took more of them on average - adding up to a threefold increase in antidepressants actually sold. The increase was seen across men and women of all ages and social classes.

There's no good evidence of an increase in mental illness in Britain in this period, by the way.

But why did the 2009 paper report no change in antidepressant users, while this one did? It could be that the increase was localized to the Tayside area. Another possibility is that there was an increase nationwide, but it wasn't about people with depression.

The 2009 study only looked at people with a diagnosis of depression. Yet modern antidepressants are widely used for other things as well - like anxiety, insomnia, pain, premature ejaculation. Maybe this non-depression-based use of antidepressants is what's on the rise.

Lockhart, P. and Guthrie, B. (2011). Trends in primary care antidepressantprescribing 1995–2007 British Journal of General Practice

On Antipsychiatry

So leading US psychiatrist Stephen Stahl is annoyed at Daniel Carlat (of the The Carlat Psychiatry Blog and many other publications.)

After first surveying the current outlook for the development of new psychiatric drugs - not good, with many companies pulling out - Stahl laments:

Undoubtedly this is to the great delight of the anti-psychiatry community, lights up the antipsychiatry blogs (e.g., Carlat, http://carlatpsychiatry.blogspot.com/), who attract the Pharmascolds, scientologists and antimedication crowd who believe either there is no such thing as mental illness, that medication should not be used, or both.



Did you know that psychiatric illnesses are pure inventions of Pharma and their experts to treat patients that do not exist with drugs that are dangerous and do not work with the purpose only of profiting themselves? Stop the profits! Make mental illness go away by legislation and committee!

Stahl ends with the warning: Be careful what you ask for. You might just get it - "it" being an end to drug development in psychiatry.



Well, I would say the same to him.



Stahl paints opponents of modern pharmaceutical industry behaviour as "antipsychiatrists". They're not. Well, he only names one of them, Daniel Carlat, and he's certainly not. Carlat edits the Carlat Psychiatry Report. Let's take a look at the latest issue:



Benzodiazepines: A Guide to Safe Prescribing - discusses benzodiazepines, including a helpful table of their doses and half-lives. Useful to someone planning to prescribe these drugs, that is, which not many anti-psychiatrists would. Says that "They work quickly and effectively for anxiety and agitation...In most cases benzodiazepines have a benign side-effect profile..." Hardly likely to please the antimedication crowd.



Update on Medications for PTSD - including a review of trials of antidepressants, antipsychotics, and more exotic drugs. Says that psychotherapy is the key to treating PTSD, but that medication can be helpful: "Getting some comfort from meds can often enable a patient to more easily face" the hard task of therapy. Not enormously pro-medication, but very far from being anti.

Combined Antidepressants No More Effective Than Monotherapy - discusses a recent study finding that starting depressed patients on a combo of two antidepressants offers no benefits over just one drug. So, the piece concludes, "We recommend never using antidepressants, and banning them all forever"... no wait, that's what it would have said if Stahl were right. It actually said "we recommend...starting with a single antidepressant". Not none.



Overall Carlat is, as far as I can see, really pretty moderate. Yes, he's been critical of certain drugs, of Pharma-influenced psychiatrists and the culture of giving doctors freebies to promote products. Nonetheless, he believes that mental illness exists, and he thinks that medication can be useful in treating it.



Maybe Stahl's right and Carlat leads a secret double life as a Scientologist. Maybe he is the reincarnation of R. D. Laing, or Thomas Szasz in a rubber mask. If not, though, branding him an antipsychiatrist shows that Stahl is unclear on what "psychiatry" is.



Psychiatry means the diagnosis and treatment of mental illness. Carlat, and indeed many other like-minded critics, are trying to improve that process by encouraging correct diagnosis and appropriate treatment.



When Carlat criticizes, say, the psychiatry textbook that turned out to have been written with "help" from a drug company, he's doing, I assume, because, as a psychiatrist who cares about psychiatry, he doesn't like seeing his field corrupted by propaganda.



This is why Stahl should heed his own warning: Be careful what you ask for.



Because Stahl seems to be asking for all the opponents of the excesses of the modern pharmaceutical industry to be opponents of psychiatry itself. At the moment, they're not. There are many, psychiatrists and others, who are trying to improve psychiatry, by protecting it from what they see as negative influences.



Maybe they're wrong about which influences are negative, maybe Pharma has had a more positive impact than they think, but even if they're wrong, they're not anti-psychiatry, they're pro-psychiatry.



However, if Stahl succeeds in painting all of these people as outside the psychiatric mainstream, he might find that psychiatry, stripped of such voices of sanity, turns into something so crazy that true antipsychiatry becomes the only reasonable option.

On Antipsychiatry

So leading US psychiatrist Stephen Stahl is annoyed at Daniel Carlat (of the The Carlat Psychiatry Blog and many other publications.)

After first surveying the current outlook for the development of new psychiatric drugs - not good, with many companies pulling out - Stahl laments:

Undoubtedly this is to the great delight of the anti-psychiatry community, lights up the antipsychiatry blogs (e.g., Carlat, http://carlatpsychiatry.blogspot.com/), who attract the Pharmascolds, scientologists and antimedication crowd who believe either there is no such thing as mental illness, that medication should not be used, or both.



Did you know that psychiatric illnesses are pure inventions of Pharma and their experts to treat patients that do not exist with drugs that are dangerous and do not work with the purpose only of profiting themselves? Stop the profits! Make mental illness go away by legislation and committee!

Stahl ends with the warning: Be careful what you ask for. You might just get it - "it" being an end to drug development in psychiatry.



Well, I would say the same to him.



Stahl paints opponents of modern pharmaceutical industry behaviour as "antipsychiatrists". They're not. Well, he only names one of them, Daniel Carlat, and he's certainly not. Carlat edits the Carlat Psychiatry Report. Let's take a look at the latest issue:



Benzodiazepines: A Guide to Safe Prescribing - discusses benzodiazepines, including a helpful table of their doses and half-lives. Useful to someone planning to prescribe these drugs, that is, which not many anti-psychiatrists would. Says that "They work quickly and effectively for anxiety and agitation...In most cases benzodiazepines have a benign side-effect profile..." Hardly likely to please the antimedication crowd.



Update on Medications for PTSD - including a review of trials of antidepressants, antipsychotics, and more exotic drugs. Says that psychotherapy is the key to treating PTSD, but that medication can be helpful: "Getting some comfort from meds can often enable a patient to more easily face" the hard task of therapy. Not enormously pro-medication, but very far from being anti.

Combined Antidepressants No More Effective Than Monotherapy - discusses a recent study finding that starting depressed patients on a combo of two antidepressants offers no benefits over just one drug. So, the piece concludes, "We recommend never using antidepressants, and banning them all forever"... no wait, that's what it would have said if Stahl were right. It actually said "we recommend...starting with a single antidepressant". Not none.



Overall Carlat is, as far as I can see, really pretty moderate. Yes, he's been critical of certain drugs, of Pharma-influenced psychiatrists and the culture of giving doctors freebies to promote products. Nonetheless, he believes that mental illness exists, and he thinks that medication can be useful in treating it.



Maybe Stahl's right and Carlat leads a secret double life as a Scientologist. Maybe he is the reincarnation of R. D. Laing, or Thomas Szasz in a rubber mask. If not, though, branding him an antipsychiatrist shows that Stahl is unclear on what "psychiatry" is.



Psychiatry means the diagnosis and treatment of mental illness. Carlat, and indeed many other like-minded critics, are trying to improve that process by encouraging correct diagnosis and appropriate treatment.



When Carlat criticizes, say, the psychiatry textbook that turned out to have been written with "help" from a drug company, he's doing, I assume, because, as a psychiatrist who cares about psychiatry, he doesn't like seeing his field corrupted by propaganda.



This is why Stahl should heed his own warning: Be careful what you ask for.



Because Stahl seems to be asking for all the opponents of the excesses of the modern pharmaceutical industry to be opponents of psychiatry itself. At the moment, they're not. There are many, psychiatrists and others, who are trying to improve psychiatry, by protecting it from what they see as negative influences.



Maybe they're wrong about which influences are negative, maybe Pharma has had a more positive impact than they think, but even if they're wrong, they're not anti-psychiatry, they're pro-psychiatry.



However, if Stahl succeeds in painting all of these people as outside the psychiatric mainstream, he might find that psychiatry, stripped of such voices of sanity, turns into something so crazy that true antipsychiatry becomes the only reasonable option.

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

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

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

New Brain Cells: Torrent, or Trickle?

An important paper just out asks, Could adult hippocampal neurogenesis be relevant for human behavior?

Neuroscientists, and the media, are very excited by hippocampal neurogenesis - the ongoing creation of new neurons in an area called the dentate gyrus of the hippocampus. This is because it was thought, for a long time, that no new neurons were created in the adult brain. It turned out that this was wrong.

There's lots of exciting suggestive evidence that the process is involved in learning and memory, responses to stress, depression, and the action of antidepressants, to name just a few, although this is controversial.

However, there's a big question which has rarely been considered: how much neurogenesis are we talking about? Are there enough new cells that it would be realistic for them to be doing important stuff, or is it just a little trickle?

The most common source of skepticism toward a functional role for adult neurogenesis is the perception that too few new neurons are added in adulthood to have a significant impact. Interestingly, this concern, while valid, is usually raised informally and rarely in the scientific literature. Very few studies have addressed this issue...

The new paper reviews the evidence. Firstly, they point out that in the hippocampus, there's a group of cells called dentate gyrus granule cells which are unusual in that activity in just a few of these cells can have big downstream consequences. And these are the cells that new born neurons turn into.

Each granule cell contacts only 10–15 CA3 pyramidal cells...a single granule cell is able to trigger firing in downstream CA3 targets...Because of this “detonator” action...a single granule neuron can potentially have a large impact despite representing only a tiny fraction of the population.

So new cells may play an important role. But exactly how many are there? They re-analyze data from their own lab in rats, and, making a few assumptions, arrive at the following rough estimate: in 3 month old rats, there are 650k "young" cells less than 8 weeks old; even in 2 year old rats (ancient, for a rat) there are 50k.

This is enough to have a big impact downstream:

Since there are approximately 500,000 CA3 pyramidal cells, and each granule cell contacts 11–15 pyramidal cells, this suggests that even in the oldest animals, each CA3 pyramidal cell could receive a direct contact from a young granule cell

That's all in rats, though. What about humans? It's hard to tell. The problem is that the best way to assess the rate of neurogenesis is to inject a drug called BrdU and then study the brain post-mortem. Unfortunately, this drug can cause cancer so you can't just give it to people for the purposes of science. The only time it's used in humans is (ironically) to help detect cancer.

However, one study did manage to look at BrdU staining in the hippocampus, using people who'd been injected with BrdU for cancer (not brain cancer) and then died. This study found, the authors say, rates of neurogeneis at least as high as in rats, considering the low dose of BrdU, the fact that the patients were old, and stressed (by having cancer).

They admit that this is just one study, and comparing doses between rats and humans is inexact. They nonetheless conclude:

Are these numbers potentially sufficient to exert a functional impact in humans? We feel that the answer to this question is an overwhelming "yes".

Snyder JS, & Cameron HA (2011). Could adult hippocampal neurogenesis be relevant for human behavior? Behavioural brain research PMID: 21736900

New Brain Cells: Torrent, or Trickle?

An important paper just out asks, Could adult hippocampal neurogenesis be relevant for human behavior?

Neuroscientists, and the media, are very excited by hippocampal neurogenesis - the ongoing creation of new neurons in an area called the dentate gyrus of the hippocampus. This is because it was thought, for a long time, that no new neurons were created in the adult brain. It turned out that this was wrong.

There's lots of exciting suggestive evidence that the process is involved in learning and memory, responses to stress, depression, and the action of antidepressants, to name just a few, although this is controversial.

However, there's a big question which has rarely been considered: how much neurogenesis are we talking about? Are there enough new cells that it would be realistic for them to be doing important stuff, or is it just a little trickle?

The most common source of skepticism toward a functional role for adult neurogenesis is the perception that too few new neurons are added in adulthood to have a significant impact. Interestingly, this concern, while valid, is usually raised informally and rarely in the scientific literature. Very few studies have addressed this issue...

The new paper reviews the evidence. Firstly, they point out that in the hippocampus, there's a group of cells called dentate gyrus granule cells which are unusual in that activity in just a few of these cells can have big downstream consequences. And these are the cells that new born neurons turn into.

Each granule cell contacts only 10–15 CA3 pyramidal cells...a single granule cell is able to trigger firing in downstream CA3 targets...Because of this “detonator” action...a single granule neuron can potentially have a large impact despite representing only a tiny fraction of the population.

So new cells may play an important role. But exactly how many are there? They re-analyze data from their own lab in rats, and, making a few assumptions, arrive at the following rough estimate: in 3 month old rats, there are 650k "young" cells less than 8 weeks old; even in 2 year old rats (ancient, for a rat) there are 50k.

This is enough to have a big impact downstream:

Since there are approximately 500,000 CA3 pyramidal cells, and each granule cell contacts 11–15 pyramidal cells, this suggests that even in the oldest animals, each CA3 pyramidal cell could receive a direct contact from a young granule cell

That's all in rats, though. What about humans? It's hard to tell. The problem is that the best way to assess the rate of neurogenesis is to inject a drug called BrdU and then study the brain post-mortem. Unfortunately, this drug can cause cancer so you can't just give it to people for the purposes of science. The only time it's used in humans is (ironically) to help detect cancer.

However, one study did manage to look at BrdU staining in the hippocampus, using people who'd been injected with BrdU for cancer (not brain cancer) and then died. This study found, the authors say, rates of neurogeneis at least as high as in rats, considering the low dose of BrdU, the fact that the patients were old, and stressed (by having cancer).

They admit that this is just one study, and comparing doses between rats and humans is inexact. They nonetheless conclude:

Are these numbers potentially sufficient to exert a functional impact in humans? We feel that the answer to this question is an overwhelming "yes".

Snyder JS, & Cameron HA (2011). Could adult hippocampal neurogenesis be relevant for human behavior? Behavioural brain research PMID: 21736900

Depression: From Treatment to Diagnosis?

In theory, medicine works like this. You get some signs or symptoms. You go to the doctor, and depending on those, you get a diagnosis. Your doctor decides on the best available treatment on that basis.

The logic of this system depends upon the sequence. A diagnosis is meant to be an objective statement about the nature of your illness; treatments (if any) come afterwards. It would be odd if the treatments on offer influenced what diagnosis you got.

An interesting paper just out suggests that exactly this kind of reverse influence has happened. The authors looked at what happened in the USA in 2003 when antidepressants were slapped with a "black box" warning, cautioning against their use in children and adolescents, due to concerns over suicide in young people.

They used the data from the annual National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS). These record data on the number of patients visiting their doctor regarding different illnesses, and what medications were prescribed if any.

What happened? The warning led to a reduction in the use of antidepressants. No surprise there, but unexpectedly, this wasn't because teens who visited their doctor regarding depression, were less likely to get given these drugs.

Actually, the proportion of depression visits, that were also antidepressant visits, was almost unchanged:

The proportion of depression visits with an antidepressant prescribed, having risen from 54% in 1998–1999 to 66% in 2002–2003, remained stable in 2004–2005 (65%) and in 2006–2007 (64%)

The difference was caused by a reduction in the number of teens getting diagnosed with depression - or rather, the number of visits where depression was mentioned; we can't tell if this meant doctors were less likely to diagnose, or patients were less likely to complain, or whatever.

This graph shows the story. After 2003, both antidepressant visits and depression visits fall, while the proportion of "antidepressant & depression" visits to the total depression visits (purple line), is constant.

The effect seen is just a correlation - it might have been a coincidence that all this happened after the black box warning in 2003. It seems very likely to be causal, though. Antidepressant use was rising steadily up until that point - and in adults, both depression and antidepressant visits rose after 2003.

It's also dangerous to pile too many heavy conclusions on the back of one study. But having said that -

Getting diagnosed with depression - at least if you're a teenager in the USA - is not just a function of having certain symptoms. The treatments on offer are a factor in determining whether you're diagnosed.

One alternative view, is that the fall in depression visits represents the fact that kids on antidepressants tend to have multiple visits - in order to monitor their progress, adjust dosage etc. So when antidepressant use fell, the number of visits fell. But if it were true, we'd presumably expect to see a fall in the proportion of visits that dealt with antidepressants, which we didn't.

This is disturbing either way you look at it. If you think the pre-2003 diagnoses were appropriate, then after 2003, kids must have been going undiagnosed with depression. On the other hand, if you think post-2003 was a welcome move away from over-diagnosis of depression, then pre-2003 must have been bad.

As to what happened to the kids who would have got a diagnosis of depression post-2003 were it not for the black box warning, we've got no way of knowing.


Why did this happen? Psychologist Abraham Maslow famously said "It's tempting, if the only tool you have is a hammer, to treat everything as if it were a nail." The history of psychiatry bears this out.

Sigmund Freud's psychoanalysis was essentially the theory that most mental disturbance was a 'neurosis' or 'complex' of the kind that's best treated by lying on a coach and talking about your dreams and your childhood, which as luck would have it, was exactly what Freud had just invented.

Along came psychiatric drugs, and suddenly everything was a 'chemical imbalance'. I've previously suggested that the invention of SSRI antidepressants, in particular, may have changed the concept of depression into one which was most amenable to treatment with SSRIs.

Recently, we're seeing the rise of the view that everything from psychosis to paedophilia is about 'cognitive biases' that can be treated by the latest treatment paradigm, CBT.

We always think we've hit the nail on the head.

Chen SY, & Toh S (2011). National trends in prescribing antidepressants before and after an FDA advisory on suicidality risk in youths. Psychiatric services (Washington, D.C.), 62 (7), 727-33 PMID: 21724784

Depression: From Treatment to Diagnosis?

In theory, medicine works like this. You get some signs or symptoms. You go to the doctor, and depending on those, you get a diagnosis. Your doctor decides on the best available treatment on that basis.

The logic of this system depends upon the sequence. A diagnosis is meant to be an objective statement about the nature of your illness; treatments (if any) come afterwards. It would be odd if the treatments on offer influenced what diagnosis you got.

An interesting paper just out suggests that exactly this kind of reverse influence has happened. The authors looked at what happened in the USA in 2003 when antidepressants were slapped with a "black box" warning, cautioning against their use in children and adolescents, due to concerns over suicide in young people.

They used the data from the annual National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS). These record data on the number of patients visiting their doctor regarding different illnesses, and what medications were prescribed if any.

What happened? The warning led to a reduction in the use of antidepressants. No surprise there, but unexpectedly, this wasn't because teens who visited their doctor regarding depression, were less likely to get given these drugs.

Actually, the proportion of depression visits, that were also antidepressant visits, was almost unchanged:

The proportion of depression visits with an antidepressant prescribed, having risen from 54% in 1998–1999 to 66% in 2002–2003, remained stable in 2004–2005 (65%) and in 2006–2007 (64%)

The difference was caused by a reduction in the number of teens getting diagnosed with depression - or rather, the number of visits where depression was mentioned; we can't tell if this meant doctors were less likely to diagnose, or patients were less likely to complain, or whatever.

This graph shows the story. After 2003, both antidepressant visits and depression visits fall, while the proportion of "antidepressant & depression" visits to the total depression visits (purple line), is constant.

The effect seen is just a correlation - it might have been a coincidence that all this happened after the black box warning in 2003. It seems very likely to be causal, though. Antidepressant use was rising steadily up until that point - and in adults, both depression and antidepressant visits rose after 2003.

It's also dangerous to pile too many heavy conclusions on the back of one study. But having said that -

Getting diagnosed with depression - at least if you're a teenager in the USA - is not just a function of having certain symptoms. The treatments on offer are a factor in determining whether you're diagnosed.

One alternative view, is that the fall in depression visits represents the fact that kids on antidepressants tend to have multiple visits - in order to monitor their progress, adjust dosage etc. So when antidepressant use fell, the number of visits fell. But if it were true, we'd presumably expect to see a fall in the proportion of visits that dealt with antidepressants, which we didn't.

This is disturbing either way you look at it. If you think the pre-2003 diagnoses were appropriate, then after 2003, kids must have been going undiagnosed with depression. On the other hand, if you think post-2003 was a welcome move away from over-diagnosis of depression, then pre-2003 must have been bad.

As to what happened to the kids who would have got a diagnosis of depression post-2003 were it not for the black box warning, we've got no way of knowing.


Why did this happen? Psychologist Abraham Maslow famously said "It's tempting, if the only tool you have is a hammer, to treat everything as if it were a nail." The history of psychiatry bears this out.

Sigmund Freud's psychoanalysis was essentially the theory that most mental disturbance was a 'neurosis' or 'complex' of the kind that's best treated by lying on a coach and talking about your dreams and your childhood, which as luck would have it, was exactly what Freud had just invented.

Along came psychiatric drugs, and suddenly everything was a 'chemical imbalance'. I've previously suggested that the invention of SSRI antidepressants, in particular, may have changed the concept of depression into one which was most amenable to treatment with SSRIs.

Recently, we're seeing the rise of the view that everything from psychosis to paedophilia is about 'cognitive biases' that can be treated by the latest treatment paradigm, CBT.

We always think we've hit the nail on the head.

Chen SY, & Toh S (2011). National trends in prescribing antidepressants before and after an FDA advisory on suicidality risk in youths. Psychiatric services (Washington, D.C.), 62 (7), 727-33 PMID: 21724784