Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Archive for July 2012

The Hidden Gorilla

gorilla hiding behind a tree

Three weeks ago What would Batman do Now covered the issue of suicide in the military – an issue that had Batman missing in action, and the Joker suffering the adverse effects of psychotropic drugs. Then along came James Holmes to the premiere of Dark Knight Rises in Aurora.

Most drugs that can cause suicide, including the antidepressants, mood-stabilizers, antipsychotics, smoking cessation drugs and others, can also cause violence. The akathisia, psychotic decompensation, or emotional disinhibition these drugs trigger that lead some to suicide, lead others to violence (see Healy et al 2006).

A medical blind-spot

There is some awareness that these drugs can cause suicide but considerable resistance to the idea. There is less awareness and even greater resistance to the idea that they can cause violence. Treatment induced violence lies in a medical blind spot – no doctor wants to contemplate the possibility that she may have had a role in the deaths of innocent third parties.

This may be the grim prospect facing Dr. Lynne Fenton. Dr Fenton we are now told had been seeing James Holmes, the killer at Dark Knight Rises in Aurora, and had seen him just a week before the killings. Given the current reliance of American medicine on medications it seems likely that medications are involved in the Aurora case.

For many the instinctive reaction to Holmes will be that he is either mentally ill, evil or a street drug addict. This makes sense. Violence is one of the associations we all make to the ideas of evil, mental illness and illicit drug use. In contrast most of us know people on antidepressants none of whom are violent. This makes it difficult to accept a link to prescription drugs. For many even raising the idea that Holmes may have been crazed by a prescription medicine is likely to sound deranged or the excuse of a bleeding heart liberal.

No other risk so hidden

But in fact there is a great deal of publicly available clinical trial (Hammad 2004, p40-41) and other data highlighting the risks of violence from psychotropic drugs. There is far more hidden data. There is in fact no other area of medicine in which there is so much hidden data on a risk that has consequences for the lives of so many innocent third parties.

With each “outing” of suppressed data lately companies have been beating their breasts about the lack of transparency “in the past” and have committed themselves to greater transparency. Here’s a chance for our major companies to prove things have changed by making the data on hostility, aggression and violence on their drugs publicly available. These data might tell us something about who is at risk, and allow us to better manage these risks. If there were a conspiracy to keep the details of all plane crashes out of the public domain, would airlines or the authorities have any incentive to make travel safer?

Instead, we are likely to see a vigorous marketing of articles that deny the possibility of a link. It takes really great science to overcome our biases. But if an article fits in with our biases (our associations), almost anything can be published, and doctors can be depended on to treat it as respectable science.

While 9 + of us out of 10 find the idea that an antidepressant might have caused Holmes to behave the way he did unbelievable, those whose lives have been touched by these issues are in a completely different position. News of another mass shooting immediately raises the suspicion that an antidepressant or related drug will be involved. And as, Rosie Meysenburg has shown on SSRI Stories, the drugs are all too often involved.

Slogan for the NRA – no drugs, no killing?

The drugs have been involved so often in campus or mall shootings that for some the surprise is that the medication question is so slow to get asked, as Peter Hitchens who is not a bleeding heart liberal has pointed out. What political considerations keep the NRA out of the debate? When Batman tells America “no guns, no killing”, there must be a temptation to respond “no drugs, no killing”.

But if Holmes turns out to have been on a drug that can cause violence, it is a quite separate matter to establish that in his case the drug he was on did contribute to what happened. It may not have. Without details of the case it is difficult to offer a view.

But this will not stop the debate in the public domain about an easier question for drug companies to control – do psychotropic drugs cause violence. And here, even though in some jurisdictions companies are legally obliged to say their drug can cause violence, a recent article in Psychopharmacology by Paul Bouvy and Marieke Liem denying the possibility of a link is certain to be marketed heavily.

Storkology 

Bouvy and Liem’s article has much in common with recent articles by Robert Gibbons in Archives of General Psychiatry (see Coincidence a fine thing & May Fool’s Day). These articles may have no links to or input from industry, but they fall on the fertile ground of a distribution system complete with public relations companies geared up to make sure that messages like this get picked up and equally that messages about problems that treatment may cause do not get heard.

When it comes to Adverse Drug Reactions (ADRs) on prescription drugs, there is no such thing as an academic debate with equal airtime for both sides, although Psychopharmacology have published a response to Bouvy and Liem’s article unlike Archives of General Psychiatry which has refused to publish responses critical of Gibbons’ articles.

Bouvy and Liem correlated data on lethal violence in Holland between 1994 and 2008 against sales of antidepressants. The drug sales went steadily up and the number of episodes of lethal violence fell, leading the authors to claim that “these data led no support for a role of antidepressant use in lethal violence”.

This is a marvelous example of what is called an ecological fallacy. An ecological fallacy is when someone claims that if an increase in the number of storks parallels an increase in the number of births that storks must be responsible for births.

Doubt is our Product

The best known example of storkology in recent years were the graphs produced by tobacco companies showing rising life expectancies and even reduced deaths from respiratory illnesses in line with rising cigarette consumption. These were produced as part of a Doubt is our Product strategy to deny the risks of smoking.

Recent sightings of storks include claims that increased SSRI use is linked to falling national suicide rates. The articles making these claims offer data from the late 1980s but disingenuously omit some key facts. One is the fact that suicide rates in most Western countries were falling before the SSRIs were launched. Another is the fact that both suicide rates and antidepressant use rose during the 1960s and 1970s when antidepressants were being given to the most severely ill people at the greatest risk of suicide. This was when suicide rates should have fallen if antidepressants have any effects on national suicide rates (Reseland et al 2008).

Autopsy (post mortem) rates are also left out. The more autopsies done the more suicides and homicides are detected. Autopsy rates rose in the 1960s and 1970s and fell from 1980 before antidepressant consumption began to escalate dramatically. The rise and fall in autopsy rates perfectly mirrors the rise and fall in suicide rates.

Why would Psychopharmacology take an article like this?

For the purposes of this argument, let’s assume the data on episodes of violence in Holland that Bouvy and Liem use is correct. This may not be the case – British national suicide rates are no longer dependable. The national figure is in essence set by a bureaucrat in London, who has scope to make the rate rise or fall as needed. Let us also assume declining autopsy rates play no part.

Before considering what else could be involved, let’s look at the shape of the argument and ask why Psychopharmacology would take an article like this. First alcohol use has increased in Holland during this period but no-one is making the argument that increased alcohol use has led to a decline in acts of lethal violence or the further Bouvy and Liem argument that this means alcohol cannot cause violence. Why not? Because, we associate  alcohol with violence.

SSRIs cause growth retardation in growing children. The clinical trial data show this retardation and the labels for the drugs mention it. During this period SSRI consumption among children has increased in Holland but the Dutch have become the tallest people in the world and are getting taller. Where is the article saying that the increasing height of the Dutch proves that SSRIs don’t retard growth?

In the case of violence, the published trials show antidepressants cause it, probably at a greater rate than alcohol, cannabis, cocaine or speed would be linked to violence if put through the same trial protocols that brought the antidepressants on the market. The labels for the drugs in a number of countries say the drugs cause violence. And there is at least one clear and well-known factor, just like autopsy rates, that can account for the findings – young men. Violence is linked to young men, and episodes of lethal violence are falling in all countries where the numbers of young men are declining.

For ADR read A Dr

Whatever Psychopharmacology were doing taking an article like Bouvy and Liem’s making claims that run counter to the warnings that are already on the drugs, without warning their readers that this was the case, from here on the game for industry is about managing associations. From conmen to hypnotists to Batman, the trick is to hold the audience’s focus so they miss something much more important in their peripheral vision field. This is what public relations companies excel at.

One of the best examples of how we can be tricked can be seen in the Hidden Gorilla video where selective attention can lead to us missing a Gorilla walking right across screen in front of us. But the very best trick must be the one that leaves us certain that serotonin reuptake inhibitors or amphetamines available on the street cause violence while in complete denial that almost identical  prescription-only drugs could do so.

In the case of prescription drugs, the key people are doctors, the Watsons. Always one step behind the smarter Holmes. While it would be nice to see Watson turn the tables for once, in this mystery Sherlock Holmes has the last line once again. It’s elementary My Dear Watson. For an ADR you need A Dr.

One Script to Rule them all

So Long and Thanks for all the Fish portrayed doctors in a rather flattering light – the victims of a tragedy. They were portrayed as losing out in a Faustian bargain when they failed to realize the hazards in making all new drugs available on prescription only. The bargain offered them a chance to entrench themselves inescapably in healthcare as the only legal source of all treatments that worked instead of having to achieve this position because of their professional values or the benefits they, rather than their drugs, might bring to the table.

Forcing people into coming to see you rather than having them come because of something distinctive you offer turns out to have been a first unwitting step toward tyranny. In the process medicine has lost its soul.

Before 1962, the acme of the medical art lay in a concern for the safety of patients. Once doctors were made the conduit for new drugs, all of which were supposedly efficacious, they lost sight of safety.

Doctors now report as few as 1% of the fatal adverse events that happen on treatment. Doctors take 10-15 years after new and notable hazards of prescription drugs are first described to finally concede that these risks may be real. Even after treatment hazards come flagged up in Black Boxes, many doctors still deny that treatment could cause the problem. Many doctors have patients who are on 10-15 drugs at the same time and for indefinite periods, a recipe for treatment induced injury and death, so that unsurprisingly Pharmacosis – treatment induced injury and death – has become a leading cause of death.

But is the Lord of the Rings saga a better analogy for what has happened than the Faust story? Prescription-only privileges are the Precious that Gollum-Smedicine clutches tightly to itself, unaware that prescriptions are the key element in the route to power of the most powerful force on earth – the pharmaceutical industry.

The marketing departments of pharmaceutical companies focus in on the ring-bearers just as the Eye of Sauron focused in on Gollum and later Frodo. Once the Eye fixes on a ring-bearer, it hypnotizes him into submission. If any demur, it directs its Black Riders (Medical Academics) to enforce compliance with its Will.

At present the focus is to the tune of roughly $60,000 per doctor per annum in the United States. Under the intensity of this gaze doctors have learnt to shun the light of disclosure and are complicit in letting the industry get away with non-disclosure of clinical trial results. Doctors have visibly shrunk the way Gollum did.

In recent years prescription-only privileges have fallen into the hands of nurses and pharmacists – a set of hobbits. They are as yet less affected by the influence of Sauron. They still hope they can put things right.

The lesson from Lord of the Rings though is that Hobbits cannot save us. However good their intentions, they too succumb to the power of the Ring. In the end it was Gollum-Smedicine desperately trying to reclaim his Precious who tumbled into the chasm of Mount MooD and in so doing saved us all.

One Script to rule them all
One Script to find them
One Script to bring them all
and in the darkness bind them
in the Land of Mordough where the shadows lie

There’s something about Mary

A paper looking at antidepressants and birth defects in Denmark has just appeared. Anyone can download it and read for themselves (Jimenez-Solem et al 2012). Its worth reading.

The published data demonstrate an increased rate of major birth defects on SSRIs which fits what almost all other studies have found. But this study also finds that women who have stopped their SSRI 6-9 months previously are at a similarly increased risk.

This has led some of the authors apparently to say that the problem may stem from the underlying depression rather than its treatment. The paper puts it in a different way – there is something about the redemption of a prescription for an SSRI that leads to birth defects.

This is an extraordinarily worrying paper – perhaps one of the scariest in recent years.

The authors make the usual point about more research being needed. No paper is perfect and in this case there are known hazards with the method (prescription redemption records) the authors have used. Prescription redemption records fail to pick up many of the people taking a drug – and this might therefore explain why in this study relatively few Danish women register as being on antidepressants.

What do the data show?

First the children born to women who are on or have been on an SSRI have a roughly doubled rate of heart defects even though many major heart defects will be terminated. The higher the dose of SSRI the woman is on, the higher the risk of a heart defect in her baby.

The risk of a neural tube defect is no higher – but almost all neural tube defects are terminated in Denmark. The rates of termination in other countries looked at are higher in women on SSRIs, so this is presumably also the case in Denmark.

In contrast, the children born to women on other antidepressants do not have this increased risk. This is a particularly interesting finding in the Danish study in that in the 1980s the Danish University Antidepressant Group (DUAG) ran studies demonstrating that tricyclic antidepressants (TCAs) work in severely depressed patients when SSRIs are ineffective. So it seems a reasonable assumption that the women in the TCA group in this study were more likely to be severely depressed than the women in the SSRI treated group but the women on TCAs do not have as high a risk of birth defects.

There is some risk of birth defects in the TCA group – not as high as in the SSRI group – but this most probably reflects the fact that some TCAs, like clomipramine and imipramine, are also serotonin reuptake inhibitors and some like desipramine and lofepramine are not. In the same way some antihistamines like diphenhydramine and chlorpheniramine inhibit serotonin reuptake and some don’t. Those that inhibit serotonin reuptake cause birth defects. Those that don’t inhibit serotonin reuptake don’t cause birth defects.

Crucially with antidepressants other than TCAs and SSRIs do not have an elevated risk of birth defects.

What’s going on?

So what’s going on in the women who have stopped antidepressants for a few months but still seem to be at high risk of birth defects?

One option was outlined in Herding Women. Maybe these women, worried about the effects of taking something that sounds as unnatural as an antidepressant, figured that they’d switch to something more natural like St John’s wort, unaware that this also comes with a high risk of birth defects and miscarriages. Or maybe they switched to an antihistamine.

But the much more worrying option is this. SSRIs have far more enduring effects on the reproductive system and its related endocrinology than they have on mood. They shrink ovaries and testes and it is this that gives rise to the loss of libido associated with their use, which can sometimes be permanent. They reduce sperm quantity and function. These drugs really do have the kind of effects on testes and sperm that masturbation was once thought to have. Masturbation never did this, SSRIs do.

Before and After SSRIs

B4-After-SSRI-pic-1

Ironically there is a striking similarity between this image and the usual image in advertisements of what SSRIs supposedly do – except of course the direction is reversed. There is no more evidence that this is the true effect of SSRIs on brain serotonin than there ever was that masturbation had the effects on semen outlined in the slide above.

Before and After SSRIs

Before and after SSRIs

Given comparably powerful effects throughout the endocrine system, effects that are far more substantial and enduring than any effects that the kinds of anxiety or depression for which SSRIs are given have on the endocrine system, it is much more likely that it is some direct effect of the SSRI that is the source of these birth defects in women than leaving their anxiety untreated has caused the problem.

Before the SSRIs came on stream, women who were diagnosed as depressed had a far more serious condition than women treated with SSRIs have now. This condition was variously called melancholia or endogenous depression. This is a condition that does lead to endocrine disturbances – raised cortisol levels – but melancholia has not been linked to birth defects.

Back to the Middle Ages

The hypothesis that there might be a link between the kind of anxiety or milder mood disorders for which women get SSRIs now – in which there is no abnormality of cortisol – to birth defects is close to unprovable. What woman isn’t anxious at some point during her pregnancy?

Creating a culture where women were told that being anxious might cause their unborn child to have a birth defect sounds suspiciously like taking us back to the Middle Ages when women were told that birth marks on the faces of their children were caused by the mother looking at a fire.

It is far more likely that the risk of birth defects in women who have stopped their SSRI is mediated through some enduring epigenetic change or effect on the endocrine system brought about by previous treatment than it is that these birth defects are caused by untreated nerves. If this is the case, it means we do not know how long women have to stop SSRIs and other serotonin reuptake inhibiting antidepressants before it is safe for them to conceive.

Few doctors inform women of child-bearing years of the risks of dependence on an SSRI.  Few inform women of the risks of birth defects on an SSRI.  What is the right thing to say in the light of the most recent evidence? What would the American Woman who haunts these posts have to say?

Herding women

pregnant woman

Since 2005, Paroxetine, first marketed by GlaxoSmithKline as Seroxat/Paxil, has carried warnings of birth defect risks. These risks led to litigation in the US – but not elsewhere. In the first case that went to court in the US in 2009, the Kilker case, the lawyers for Lyam Kilker argued that, even before Paxil was launched, there was good laboratory evidence that the SSRIs might cause problems, and, that following their initial marketing, further evidence had emerged steadily from 1998 onwards painting a consistent picture that the drugs actually do cause problems in clinical use, and of company efforts to hide this.

Glaxo

Yet since their launch Paxil and other SSRIs have been actively and increasingly promoted to women of child-bearing years. The company most committed to this and most effective at it was Glaxo.  This is ironic in that the company began in New Zealand as the makers of formula milk for babies – from which they derived their name.

Women of child bearing years in particular who have nervous problems have been encouraged to go to their family doctors where they are all too readily put on an SSRI. These family doctors aren’t aware of the risks of dependence or birth defects, and so don’t warn. The patients become dependent on the SSRI and find it impossible to stop using it when they wish to get pregnant or if they find they are pregnant. In an age where most women will abstain from alcohol, nicotine, tea, coffee, soft cheeses or uncooked meats if they are thinking about becoming pregnant, few of these women would consent to treatment if informed of either the risk of birth defects or the risk of becoming addicted (see We need to talk about doctors).

Grooming

What we are seeing here is the astonishing marketing power of pharmaceutical companies, which can now bring about huge changes in medical culture within months. In this case, a great part of the scientific literature (the primary marketing tool of companies) on the use of antidepressants in pregnancy and on dependence on antidepressants is ghostwritten – just as virtually all literature on giving antidepressants to children was, at one point, company or ghost-written.

Because of this, even the most independent guideline makers like NICE, who can only go by the published literature, are trapped. Regulators, like the FDA in the US and MHRA in the UK, which reflect a professional consensus rather than lead on issues like this, are likewise maneuvered into a corner. Doctors, who should be leading and who until recently would have been hostile to the idea of taking antidepressants in pregnancy, believe their role is to follow NICE, the FDA and what appears to be the scientific evidence and have failed to spot how they are being groomed.

The process of manufacturing clinical consensus has become so slick that it is now almost impossible to find independent articles from academic physicians that will sound a note of caution about prescribing antidepressants to women of child-bearing years. This is a problem that increasingly applies across all of medicine – from the use of drugs for osteoporosis, respiratory or gut problems, or for pain-relief, as well as all psychotropic drugs.

Where once drugs were seen as poisons to be used judiciously and with caution, they are now treated as fertilisers whose more or less indiscriminate use can only do good.

Eye of Newt, Toe of Frog, Leaf of Hypericum?

And here’s the rub. In these legal cases, the laywers for GlaxoSmithKline took care to ask any of the women who were suing whether they had had St John’s wort (Hypericum). If they had they were likely to face an action from the company to get their case thrown out on the basis that this serotonin reuptake inhibiting plant had been known for centuries to cause birth defects.

Farmers regard St John’s wort as a dangerous weed and know to keep their cattle and sheep out of fields in which the weed grows for fear of miscarriages. But under industry influence doctors have been used like the dogs a farmer uses to round up sheep to herd women in exactly the opposite direction.

How many birth defects, miscarriages and terminations? 

There are roughly 700,000 births in the UK each year, 4 million in the USA. Close to 10% of these, 70,000 in the UK and 400,000 in the US, will now be to women on antidepressants. Normally 2% of women give birth to a baby with congenital defects. So there should be 1400 babies with congenital defects born to women on antidepressants in the UK, 8000 in the US, but in fact the figures show that 3% or more of the babies born to these mothers,  2,100 in the UK and 12,000 in the US, will have major congenital defects.

There are likely 50-60,000 miscarriages in UK each year, 400,000 in the USA. In women on antidepressants this rate appears close to doubled – so what would have been 5-6,000 miscarriages in women on antidepressants will more likely be  10,000 in the UK, and 40-50,000 becomes something closer to 80,000 in the USA.

There will also be a substantial increase in voluntary terminations of pregnancy. This can happen for a few reasons. In some countries, any evidence of neural tube defects or other major congenital abnormalities automatically leads to a termination (see American Woman, and American Woman 2). In other instances, the disinhibiting effects of SSRIs may lead to a woman having a termination she might not otherwise have.

There are roughly 250 terminations per 1000 live births. In women on SSRIs this likely rises to somewhere around 400. A very high proportion of terminations after 16 weeks are likely to be women on or previously on SSRIs, for reasons outlined above.

Glaxo began life making baby milk. SmithKline were once SmithKline Beecham. Beecham made their early money out of Beecham’s Pills. Slightly over a hundred years ago they were censured by the British Government for apparently promoting their pills for “maladies of indiscretion” – they would induce miscarriages.

A new epidemic

pregnant woman

This post is by Dr Adam Urato, a Professor of Obstetrics & Gynecology at Tuft’s University

Imagine for a moment that a virus started affecting about 5% of all pregnant women—200,000 US pregnancies per year. Imagine that it caused significant pregnancy complications–more than 10% of those infected with the virus would have miscarriage, up to 20% or more would have preterm birth, and 30% of newborns would show effects of the exposure in the days after birth—sometimes severe, with seizures and trouble breathing.

  it would be a public health emergency

If this were to occur it would be considered a public health emergency and a tremendous effort would be put forth to address it. Yet this epidemic is happening and, in many ways, it is going unrecognized. Pregnant women and the public are unaware. It is the epidemic of antidepressant drug exposure during pregnancy.

Two articles came out recently showing that antidepressant use by pregnant women is associated with preterm birth (1, 2). One of them also showed increased rates of neonatal seizures in newborns who were exposed to antidepressants in utero. These articles join a large and growing body of literature that clearly demonstrates risks when pregnant women use antidepressants (3).

These risks are all the more concerning given that there is no evidence of improvement of pregnancy outcomes with the use of antidepressants by pregnant women. There is an important question to ask: Are we exposing millions of pregnant women and their babies to a class of drugs that are causing significantly more harm than good?

the downside

Current research suggests that antidepressant use (typically the SSRIs) by pregnant women is associated with increased risks of miscarriage (4), birth defects (5), preterm birth (1, 2), preterm premature rupture of membranes (6), preeclampsia (7), and decreased fetal growth (8). After birth, newborns who were exposed to antidepressants in utero have increased rates of what is called the newborn behavioral syndrome (9) which can consist of a variety of symptoms including tremors, agitation, excessive crying, respiratory difficulties, and seizures (1). Exposed newborns also have been shown to have changes in heart conduction (10) and a potentially fatal condition called Persistent Pulmonary Hypertension of the Newborn (PPHN) in which the arteries to the baby’s lungs are constricted leading to trouble breathing or, in severe cases, death (11).

Many of these risks are not rare. Rates of miscarriage in women taking antidepressants are estimated at greater than 10% (12). In some studies rates of preterm birth in the antidepressant exposed groups have been greater than 20% (13, 14). Ten percent of babies exposed to SSRIs in utero will show the prolonged QT syndrome on their EKG (10). And up to 30% of exposed babies will develop the newborn behavioral syndrome (9).

we are witnessing a large uncontrolled experiment on human development

What is particularly concerning in this area is the issue of possible long term effects on the developing brains of exposed babies. Developing embryos and fetuses are loaded with serotonin receptors and the serotonergic system plays a crucial role in fetal development. What happens to human development of the brain and behavior when we alter this system? We simply have no idea and we are currently witnessing what amounts to a large uncontrolled experiment on human development. The current research data is not reassuring. Animal data clearly shows that fetal exposure to antidepressants can lead to changes in the development of the brain and changes in behavior (15, 16). Studies are available that demonstrate effects on the branching of neurons–the basic cell in the nervous system (17). Human studies have shown that children who were exposed to antidepressant in utero have changes in motor development and behavior (18, 19). Last July (2011) researchers at Kaiser in California showed a doubling of the risk of autism with prenatal exposure to antidepressants (20). And this doesn’t appear to be a “chance” finding. For decades serotonin has been implicated in the etiology of autism (21).

there is no evidence of benefit

Many of these risks might be tolerable if there was evidence of pregnancy benefit with the use of antidepressants by pregnant women.  “After all,” you might think, “cancer drugs have risks too but we use them because they cure cancer.” But, sadly, there is no evidence of obstetrical benefit with the use of these drugs by pregnant women. In study after study the group of women on the antidepressants have worse pregnancy outcomes, not better. For example, they have more miscarriages, more preterm birth, and more neonatal complications.

For years, the key opinion leaders in this area (most of whom are paid sizeable amounts by the drug industry) have been pitching the idea that pregnant women, by taking antidepressants, will improve their mood and that this will lead to better pregnancy outcomes. The conventional wisdom has been that depression is like diabetes and depressed pregnant women need to stay on their antidepressants just like pregnant diabetics need to take their insulin. And this counseling gets repeated on a daily basis in doctors’ offices around the globe and in news reports on this topic.

The problem is that it just isn’t true: pregnancy outcomes do get better when diabetics take their insulin but this isn’t true with antidepressants. We had all hoped that the pregnancies of depressed women could be helped with drugs, but the scientific literature does not support the idea that antidepressant use in pregnancy improves outcomes. In fact, it’s just the opposite. When you take a group of depressed pregnant women and compare them to depressed pregnant women taking antidepressants, it’s the group that is taking the antidepressants that has the increased rates of pregnancy complications.

what women need is accurate, correct, and complete information

So what should we tell pregnant women and women of childbearing age who are taking these drugs? As a Maternal-Fetal Medicine consultant, I deal with this issue regularly. And for me the key is transparency and properly informing the patients and the public. Who can argue with giving pregnant women full information about a drug they are taking? And the truth is that full information in this area means telling women that antidepressant use during pregnancy has been associated, in study after study, with pregnancy complications and no evidence of better pregnancy results.

I frequently give lectures on this topic and am asked “What about the woman with severe depression who is suicidal when she comes off her antidepressant?” To me, it sounds like she should stay on the medication. But, let’s be clear, the vast majority of women on these drugs have mild to moderate depression. Furthermore, my main point on this is not that we should be telling anyone what to do. Psychotropic medication use during pregnancy is a personal choice and these women need care and support. But what they also need is accurate, correct, and complete information so they can make an informed decision; that is not what is currently happening.

We are currently seeing what amounts to an epidemic of antidepressant drug exposure during pregnancy and there is a pervasive lack of public information and understanding on this topic. Pregnant women need accurate information about drugs they take. I am surprised on a regular basis by my colleagues in obstetrics and psychiatry who are simply unaware of the large body of scientific studies clearly showing antidepressants to be associated with pregnancy complications. What pregnant patients choose to do with this information is up to them, but patients and the broader public deserve to be told the truth about the risks of antidepressant use during pregnancy.

References:

1. Hayes, R.M., Wu, P., Shelton, R.C., Cooper, W.O., Dupont, W.D., Mitchel, E., Hartert, T.V., Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies, American Journal of Obstetrics and Gynecology (2012), doi: 10.1016/j.ajog.2012.04.028.

2. Yonkers KA, Norwitz ER, Smith MV, Lockwood CJ, Gotman N, Luchansky E, Lin H, Belanger K.  Depression and Serotonin Reuptake Inhibitor Treatment as Risk Factors for Preterm Birth.  Epidemiology. 2012 May 23. [Epub ahead of print]

3. Urato AC.  Antidepressants and Pregnancy:  Continued Evidence of Harm—Still No Evidence of Benefit.  Ethical Hum Psychol Psychiat 2011; 13: 190

4.  Nakhai-Pour HR, Broy P, Bérard A.  Use of antidepressants during pregnancy and the risk of spontaneous abortion.  CMAJ. 2010 Jul 13;182(10):1031-7. Epub 2010 May 31.

5. Colvin L, Slack-Smith L, Stanley FJ, Bower C. Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy.Birth Defects Res A Clin Mol Teratol. 2011 Mar;91(3):142-52. doi: 10.1002/bdra.20773. Epub 2011 Mar 4.

6. Reis M, Källén B.  Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data.  Psychol Med. 2010 Oct;40(10):1723-33. Epub 2010 Jan 5.

7.  Toh S, Mitchell AA, Louik C, Werler MM, Chambers CD, Hernández-Díaz S.  Selective serotonin reuptake inhibitor use and risk of gestational hypertension.  Am J Psychiatry. 2009 Mar;166(3):320-8. Epub 2009 Jan 2.

8. Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C.  Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data.  Arch Gen Psychiatry. 2006 Aug;63(8):898-906.

9. Levinson-Castiel R, Merlob P, Linder N, Sirota L, Klinger G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006; 160:173-176.

10. Dubnov-Raz G, Juurlink DN, Fogelman R, Merlob P, Ito S, Koren G, Finkelstein Y.  Antenatal use of selective serotonin-reuptake inhibitors and QT interval prolongation in newborns.  Pediatrics. 2008 Sep;122(3):e710-5.

11. Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, Nielsen RB, Nørgaard M, Stephansson O, Valdimarsdottir U, Zoega H, Haglund B.  Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries.  BMJ. 2012 Jan 12;344:d8012.

12. Hemels ME, Einarson A, Koren G, Lanctôt KL, Einarson TR.  Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis.  Ann Pharmacother. 2005 May;39(5):803-9. Epub 2005 Mar 22.

13. Ferreira E, Carceller AM, Agogué C, Martin BZ, St-André M, Francoeur D, Bérard A.  Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates.  Pediatrics. 2007 Jan;119(1):52-9.

14. Latendresse G, Ruiz RJ.  Maternal corticotropin-releasing hormone and the use of selective serotonin reuptake inhibitors independently predict the occurrence of preterm birth.  J Midwifery Womens Health. 2011 Mar;56(2):118-26.

15. Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA.  Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.  Science. 2004 Oct 29;306(5697):879-81.

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19.  Pedersen LH, Henriksen TB, Olsen J.  Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age.  Pediatrics. 2010 Mar;125(3):e600-8. Epub 2010 Feb 22.

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What would Batman do now?

Johanna Ryan in her post Dependence Day points to serious problems linked to psychotropic drug use in the military and what seem to be recent alarming developments, but there is a 60 year history here.

In the 1950s, the VA hospital system commissioned Norman Farberow to look at rising rates of suicides among veterans. He studied veterans hospitalized for either medical or psychiatric conditions during the periods 1950 through to the mid1970s. The 3 figures below bring out the findings.

Figure 1 shows a set of fluctuating suicide rates year on year for veterans admitted to medical beds. The rates are higher than national suicide rates but these rates and their fluctuations are in keeping with what might have been expected in a set of younger men. The increases in the late 1950s and early 1970s may mirror the effects of the Korean and Vietnam wars, or perhaps other social factors or they may be entirely random.

Figure 1

Figures 2 and 3 are strikingly different to Figure 1. Figure 2 does not show the expected fluctuations linked to social factors or any randomness. It shows a steady rise in suicide rates in those who have been hospitalized for a mental condition. Until 1955 the rates are identical to the rates found in those hospitalized for a general medical condition.

But as of 1955, they start climbing in an uninterrupted fashion. The rises and falls we see in Figure 1 that might or might not be linked to social factors such as the Korean war are not there. This can be seen clearly in Figure 2 when the two sets of figures are superimposed and again in Figure 3 which show admissions to psychiatric beds on their own.

 

 Figure 2

 

 

 

Figure 3

 

 

 

 

 

 

 

 

 

Why the bifurcation in 1955? This was the year of the introduction of chlorpromazine. Year on year after 1955 a greater number of tranquilizers (antipsychotics / neuroleptics) like chlorpromazine were consumed by veterans with mental health problems as an ever greater number of these drugs were marketed. These drugs were given to veterans who were depressed, anxious or psychotic – they were not as might be thought now restricted to veterans who were schizophrenic.

But as Johanna Ryan brings out, they were almost certainly not given at that time to soldiers returning to the theater of war. She calls on us to stand together and bring about improvements. We have to stand together but whether it will bring about improvements is another matter. The Department of Defense for instance know that the literature about most of the drugs being given to troops now is ghostwritten and that the excess of suicides and violent acts there have been in clinical trials of these drugs have been airbrushed out of publications. But even they seem hypnotized.

Patients complain that the wrong drug in the wrong dose makes them zombies, but it seems everyone else in the policy apparatus who has anything to do with authorizing the use of these drugs is also marching zombie like to the one tune – like North Koreans in fact.

When the wife of Randall Tobias who was CEO of Lilly at the time controversy first blew up about Lilly’s Prozac causing suicide gets put on Prozac and commits suicide and it makes no difference, it gets harder and harder to see a way out. Why so serious? Well even Heath Ledger has either committed suicide or died in the night from a drug interaction. Is this Batman’s stickiest moment?

Ominously there is no sign of Batman anywhere.

If Robin were still around he might say “Holy Healthcare Reform – someones killing our Veterans, what would Batman do now?”

The very last thing to do is what Batman offered Mr Freeze: “Give yourself up. We can get you help – medical help” (see So Long and thanks for all the Fish).

But the Cheshire Cat got the Robin. It left however a grin behind in a phrase that lingers – the opposite of a girl is a boy. For all complex problems, its better turn to Catwoman – Michelle, or Ann?  Or maybe Angela?

References

Farberow N, Ganzler S, Cuttler F et al (1978). Status of Suicides in Veterans Administration Hospitals. Reports 2-4. Los Angeles, CA: Central Research Unit, V. A.Wadsworth Hospital Center.

Dependence Day

Author: Johanna Ryan, Labor Activist with Illinois Workers Compensation Lawyers (Chicago) 

Last month I watched as forty Iraq and Afghanistan vets led an antiwar march to the gates of the NATO summit in Chicago, and handed back their medals. At the rally, they described the toll the wars had taken on the troops as well as the people of Iraq and Afghanistan, and demanded their “right to heal.” Chief among the problems on their minds were post-traumatic stress disorder, suicide … and psychotropic drugs.

“It’s really appalling that when our brothers and sisters get home and they ask for help, the only help they can get is some type of medication, like Trazodone, Seroquel, Klonopin— medication that’s practically paralyzing, medication that doesn’t allow them to conduct themselves in any type of regular way,” veteran activist Aaron Hughes told Democracy Now. “And yet those are the same medications that service members are getting redeployed with, and conducting military operations on, and the same medications that we are trying to reintegrate into the world with.”

Facing the Fog of War through a Fog of Drugs 

Conducting military operations? On Seroquel? There must be some mistake, I thought. But a little research confirmed Aaron’s accounting: the United States armed forces are increasingly marching on pharmaceuticals. Twenty percent of active-duty troops are on psychotropic medications, including 17% of the combat troops in Afghanistan.

The results are not pretty. Eighteen vets commit suicide each day. The Veterans Administration reports 1,000 suicide attempts, and 10,000 calls to its suicide hotline each month. Last year, 301 active-duty soldiers took their own lives. A 2010 Army internal report on the suicide crisis estimated that prescription drugs were involved in one-third of soldier suicides. Their estimate is probably conservative. “We have never medicated our troops to the extent we are doing now …. And I don’t believe the current increase in suicides and homicides in the military is a coincidence,” said Bart Billings, a former military psychologist who hosts an annual conference at Camp Pendleton on combat stress. (“A Fog of Drugs and War,” Kim Murphy, Los Angeles Times, April 7, 2012.) Rates of domestic violence, murder, child abuse and other violent crimes are also rising in military base communities across the nation.

Clearly there are multiple reasons for this epidemic. The Iraq and Afghanistan wars themselves are the bedrock cause. The stress increases as soldiers are forced into second, third and fourth combat deployments. However, the military’s increasing reliance on drugs has at best failed to “manage” a grim situation, and may have made it worse.

Zoloft and a Rifle

Prior to 9/11, the military did not send soldiers into combat on psychotropic drugs. In many cases, they were a bar to serving in the military at all. But as the Iraq and Afghan conflicts expanded and multiple combat deployments became the rule, the military embraced the idea that medications could keep troops “deployable.” Drug companies took their place in the military-industrial complex, positioning their products not just as medicine for wounded veterans, but as fuel that could keep exhausted and traumatized soldiers on the battlefield.

SSRI antidepressants became widely prescribed for symptoms of post-traumatic stress disorder as well as depression and anxiety.  The evidence that this was good medicine was thin, especially for patients being medicated and sent back into a traumatic situation. All these drugs carry warnings that they can cause agitation, hostility and suicidal and homicidal impulses. In 2007 the FDA expanded its suicide warning for children and teens to include young adults ages 18 to 24 – the group that forms the backbone of the Army. “All of these drugs increase suicide risk, which is why it’s probably not good to give it to guys who carry guns,” said Brown University professor David Egilman. By 2007, one in eight soldiers surveyed in Iraq and one in seven in Afghanistan said they had taken sleeping pills or antidepressants.

The careful monitoring needed to use these drugs safely just doesn’t exist in a war zone. While the Pentagon insisted that medicated troops were only deployed after they’d been “stabilized”, many were on a plane to Iraq or Afghanistan within four weeks of getting their prescriptions. Soldiers suffering from acute stress in combat have often been prescribed drugs and returned to the front lines in as little as three days. (“A Potent Mix: Zoloft and a Rifle,” Lisa Chedekel and Matthew Kauffman, Hartford Courant, May 16, 2006). Therapy is often totally unavailable, and mental health staffing is so short that psych evaluations and “monitoring” is often done by videoconference.

A total mental breakdown

In the PBS Frontline documentary The Wounded Platoon, young soldiers from Fort Carson, Colorado shared their experiences during the 2006-2007 surge: “I was having, like, a total mental breakdown,” said Kenny Eastridge; “…They put me on all kinds of meds too, and I was still going out on missions. They had me on Ambien, Remeron, Lexapro, Celexa, all kind of different stuff. They tried different medications at different doses and nothing would work.” When stationed away from the base, Eastridge said, he would run out of meds. “It was hard to find someone who wasn’t on Ambien,” recalled medic Ryan Krebbs. “It helps you sleep. It also gets you pretty high. You have trouble remembering things. It lowers your inhibitions, all that stuff. They shouldn’t give soldiers Ambien in Iraq.”  Several soldiers told Frontline that their platoon became trigger-happy, opening fire on Iraqi civilians for any reason or no reason.

More recently, Army doctors have found what they thought was a better fix for the  insomnia, nightmares and rages of soldiers under stress from multiple deployments: antipsychotics, chiefly Seroquel. Pentagon spending on Seroquel doubled from 2003-2007, with larger increases in demand for the highest doses.

Spending on Topamax, an anti-convulsant, quadrupled as military doctors added it to the cocktail for thousands of soldiers diagnosed with traumatic brain injuries. And a rising number of active-duty troops were returned to duty on Oxycontin, Percocet and other narcotic painkillers. Meanwhile, in an effort to keep its medicated troops from running out of pills in theater, the Army’s Central Command authorized soldiers to ship out for Iraq and Afghanistan with 180-day supplies of their medications – making it all too easy to swap and share meds, or to take double doses on a bad day.

When death comes in the night

In 2008, in separate incidents, four young veterans in West Virginia died in their sleep from multiple drug toxicity. Twenty-three year old Andrew White was on a cocktail that included Klonopin, Paxil, opoid pain medications and up to 1,600 mg of Seroquel per day. In the weeks leading up to his death, Andrew gained forty pounds and suffered from tremors, slurred speech and disorientation. His father, Stan White, claims to have identified eighty-seven similar deaths among soldiers on Seroquel.

Veterans and their families are rebelling against this grotesque system of “care.”  They have had some small victories – the VA recently announced it would hire another 2,000 mental health staff, and the Department of Defense placed some restrictions on use of Seroquel by active-duty personnel – but much more is needed. If the rest of us support their fight for humane and effective care from the VA, perhaps it could become a model for the civilian mental health system we desperately need.