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 February 2012

The story of SSRI stories

 

Rosie Meysenburg’s story

For anyone interested in the effects of drugs, the website SSRI stories has been an inspiration. Rosie Meysenburg, its creator, was recently diagnosed with cancer and is terminally ill. The story of how she came to create SSRI stories shows what people can do to hold the powers that be to account.

—David Healy


 

DH:          How did you get started with SSRI stories ?

RM:          I had spent ages trying to quit smoking. Eventually, in 1992, my doctor persuaded me to try Prozac. I took it for eight weeks during which time my behavior got stranger and stranger and I ended up in hospital. I had no idea what caused the problem until my husband, Gene, suggested it might be the Prozac. So I called the Mental Health Association here in Dallas and asked, “Do you know anyone else who has had a reaction to Prozac? Is there somebody I could talk to?” She said, “Oh, we have a number here for the Prozac Survivors Support Groups.” So she gave me their number and I called them. They talked to me for a long time on the phone and sent me a ton of literature. Well I couldn’t believe it — there were testimonies from Dr. Teicher and others.

I had a manic reaction to Prozac taken for smoking cessation.

I got my medical records and they showed the doctors thought I had a manic reaction to Prozac although I don’t think it was manic; I think it was more nutty. I was angry about the fact that they knew it was the drug but hadn’t told me but there wasn’t too much I could do then — this was 1993. After that I wrote a letter to the FDA which they used in Motus vs. Pfizer — a letter that asked if they could put the same warning on their package insert as Germany had.

Then the Internet started in 1997 and I sat down and I went through the phone book and I called practically every physician in the city in which I lived. I’m a determined person. I asked them if I could find anything about Prozac on the Internet that would show that it could cause harm would they be interested? About 22 of them said yes they would be. I went into Alta Vista — the search engine before Google — I typed in Prozac. There wasn’t too much else you could type in except Zoloft and Paxil. And sometimes I’d put “plus suicides” or “plus murder” whatever and I came up with all kinds of things. This is how I started my message board — it was to these people and some of them were very interested, which kept me going.

Then Mark Miller who lost his 13-year-old son to a Zoloft-induced suicide became involved. He put up a website for Ann Tracey — I didn’t really know who she was. I found her on the Internet and so I sent her some emails and she wrote back. She said, “The Zoloft suicides? Can you find a phone number for these people, Rosie?” So I had a domain where you can find phone numbers and I found them and she called them and told them what had happened to their children. We had a whole list of phone numbers. We did that until about 2004.

Ann started pursuing another line of business although she still tried to find time to help on the SSRI cause. But then the FDA announced online — we watched the FDA announcements like a hawk — a meeting concerning antidepressants/suicide and children. We had about 25 names of parents of children who had committed suicide.

The FDA was astounded.

I think the FDA was astounded. They started out with the five minutes they were going to give to each parent to present their case. Then they went to three minutes and finally two minutes. I mean the FDA has these meeting every day and two or three people show up for issues like how many nuts should we put in the cookies? If you’re allergic to peanuts, what should the warning be? I think by law they are required to put an FDA meeting notice in one newspaper and they happened to put it in the Arlington, Virginia, newspaper because my husband Gene talked to a man whose son had committed suicide who saw the FDA announcement in the newspaper and then pretty well everybody came from either finding out about it by themselves or from contact through Ann Tracey, Mark Miller, or myself.

So we went to the 2004 meeting and the FDA placed a black box warning regarding suicidality and children under the age of 18, and then in 2006 that same black box warning for the 24-year-olds and under. I looked at my computer in my saved box and I had 1,000 messages; probably 300 were suicides and another 250-300 were murders, and then there were assaults and all kinds of different things.

DH:          When was this?

RM:          This was May 2006. I had over 1,000 media articles regarding antidepressants and murder, murder-suicides, suicides, assaults, school shootings, road rage, air rage, etc. My husband Gene set up the initial database for me.

“Thank you. I understand now what happened.”

I spent probably 20-25 hours a week doing that and the rest of time I spent with family and friends. I posted every post that’s up there. Can you believe it — 4892! Curious the way I feel about SSRI Stories. On the contact page for SSRI Stories everybody thanked me. I said to Gene that there will be a lot of people just saying, “Oh you’ve got to be kidding me; this cant be true.” Instead I’ve received these emails from the contact page of SSRI Stories with people saying “Thank you. I understand now what happened to my brother or my sister.”

When I first started my message forum I got a threatening letter from somebody when I had my own name up there, although I still kept up with my message board. Now that I’m dying I guess I’m less worried about them beating up on me over Prozac you know. I used to be worried about all these shooters out there but now I don’t care who knows my name.

Now that I’m dying I guess I’m less worried about them beating up on me over Prozac.

I am pretty sure FDA have ignored SSRI Stories. But when I look at the stats, Homeland Security goes in there quite a bit and looks at some of the cases. A lot of people are coming in from the military. The big thing I’ve had is people making comments on sections because my stat counter gives the web address. For instance one comment said, “My friend John Smith didn’t know why we were having all these school shootings and he went into SSRIs Stories and now he knows why.” I think it’s helped raise awareness, and I see a lot of people making comments because they come up in the stat counter with the URL or their website and I can click on their website and they’ll say things like, “Have you seen SSRI stories? It’s unbelievable but I think it’s true.” Stuff like that.

So I don’t know how many people have actually looked at SSRI Stories. As far as the index goes we’ve had maybe 300,000 or 400,000 people look at it, which isn’t a lot but which is still quite a bit. On the individual stories we’ve had close to 1 million people looking at them. It seems like in the individual stories approximately one out of every four people will go from the individual story into the index or cover page.

more people are being injured out there by this than we realize

But I can’t really say what kind of impact SSRI Stories has had. What I feel is that more people are being injured out there by this than we realize. Someone I know told me he has a neighbor on one side just died on Paxil and Zoloft, while on the other his neighbor just died on Celexa. Before that neighbor died she said she thought the police were taping her and she had begun to drink heavily and to act crazily.

DH:          Did your friend not know your work and warn his neighbors?

RM:          Well he only found out afterward. He could see the personality of one of his neighbor’s change but he didn’t know for sure and he felt he couldn’t go into it in-depth because this was his neighbor and he was embarrassed. Beside even when I was on Prozac I failed to spot the connection.

One day I went up to the bank and there was a lady there. She began talking about Prozac to me and she said that when she was on Prozac she killed her dog and then, right there at the bank counter, she started crying. I said “Why did you kill your dog?” and she said that he’d become incontinent and all of a sudden on Prozac she got aggravated with that so she took him to the vet and had him put to sleep. And then she started crying. She said her dog was her best friend. And I said to her, “ What was it about the Prozac that made you do this?” And she said it made her more aggressive. It makes you more unfeeling and more aggressive. Of course, she only had her dog put to sleep. I’m not saying she committed a major crime. Her pet was incontinent. He was probably old and would have died soon anyway but the point is that this is happening to a lot of people.

He burned down 10 churches and…will spend the rest of his life in jail.

About two or three months ago there was a case in a town near Dallas where a 20-year-old man, who was taking Champix and Prozac at the same time, went around in the middle of the night and burned down 10 churches.  No one of course had been killed because the churches were empty but the jury gave him life in prison. This article on SSRI stories talks about Prozac and Champix and it does say the perpetrator blamed the Champix because he didn’t know if he’d actually done it or if he’d dreamed it. But you see the Prozac can cause you to kind of go into a manic rage also and out of this you get a pyromania, or a kleptomania or nymphomania, and then on the Champix he was kind of like in a dream state. Anyway he’s 20 years old and will spend the rest of his life in prison.

DH:          Why did the issue of people becoming violent get your attention?

RM:          Well because you know in United States it’s always been a tradition not to print suicides. The only way you can tell is if they have a little clue in the obituary or if it says “he died suddenly.” Whereas, the UK and other countries do print suicides. They’ll say “committed suicide.” That’s why I have so many cases from people in Australia and Canada of suicides but very few from the US. However if it’s a controversial suicide or suicide of a famous person, people will want to know what happened to them, and then they’ll print it because everyone will say “Oh my gosh, this famous actor died. How did he die?” But I’m just talking about ordinary people who aren’t high profile. Also the big problem in the US is the drug advertising and of course the media is dying. Some of the newspapers have gone out of business — the only thing that keeps them alive is the drug ads.

The US has lost Freedom of the Press in an unusual way.

The U.S. has lost Freedom of the Press in an unusual way. The newspapers and TV cannot mention that the perpetrator was on an SSRI because the media is afraid the pharmaceutical companies will pull their ads.

DH:          Why do you think people are so reluctant to think that the drugs may be causing a problem?

RM:          I think it’s because they don’t ever stop to think that it might be the medication. I mean in the sense that I was on Prozac for nine weeks while I was losing my mind but I never once thought of the Prozac. My husband, Gene, was the one who finally figured out what was happening to me.

Why are we so slow to finger the drug?

DH:          Why are we so slow to finger the drug?

RM:          Because we’ve never really had a prescription drug before that’s caused so much violence and murder and mayhem. We’ve had the antibiotics for years and, of course, the illegal drugs. They were mostly made illegal because they were addictive, but we often think they cause psychosis, especially cocaine and methamphetamines. Pretty potent. However none of the school shooters were on those illegal drugs. That’s something.

DH:          Why, given so many school shootings being linked to these drugs, do you think the coin hasn’t dropped? What is it about the United States that makes people so reluctant to think the drugs could be responsible?

RM:          They say that in United States anybody who wants to can have a gun. So they blame the guns. And we did have one school shooting where the person was not on an SSRI in Kentucky and reporters write about this case all the time but neglect to mention the other school shooting. Strange. In Columbine, that second kid Dylan Klebold’s records were sealed, so nobody knows his toxicology. But you know there have even been 3 or 4 girls that did these shootings. And not all of the 65 school deaths were shootings — some were stabbings. And nobody seems to catch on. I don’t want to say nobody because while I go to my other stat counter, Go-stats, I’m amazed at the number of people that have typed in the words “antidepressant plus school shootings,” but there’s nobody in power seeing this.

Bill O’Reilly says there is an epidemic of women school teachers molesting their male students.

Bill O’Reilly, a famous TV talk show host, says there is an epidemic of women school teachers molesting their male students. He says that his program receives at least one report a week. SSRI Stories has 16 media articles of women school teachers who molested their male students while on medications for depression. One case, in Canada, was even a “won” case in the sense that the jury decided the SNRI Effexor had caused this type of weird nymphomaniac behavior.

We have won 29 legal cases so far, that we know about. If you go into SSRIS stories cover page and click on won cases you can see them all there. About 8 were homicides and 12 were murder attempts. One was an air rage case in a diplomat from England. There was a very early Zoloft case and a murder that was won 1994 that I found in the archives. Nobody had heard about it. It happened in South Carolina. So that means at least 29 judges or juries have decided to acquit on the grounds that the antidepressant caused the criminal behavior.

The other thing that gets me about these SSRIs is, not only do people become violent, they become extremely violent especially the women. They become so terribly violent they will stab somebody 200 times. There was the case in England of the man who stabbed his wife 200 times and then walked next door and stabbed his neighbor’s furniture another 200 times. So this is what’s kind of scary about it. We have about six people on death row here in United States, I think four of them are women who killed their children while they were on Prozac or Zoloft or something. One was a physician’s wife out in California and she killed her three children and then tried to kill herself and didn’t die and now she’s on death row.

DH:          Do you think there’s anyway for us to raise the profile of these cases and create a resource for people to get help?

RM:          That’s another bothersome issue — nobody’s put up a list of attorneys or physicians or anything. I did ask one or two people to help me post but nobody wanted to — they’re all so busy. Everyone’s so busy and it takes a lot of time. I can’t do the kind of work it would take to set up a list of physicians or attorneys but in future time somebody might be able to set that up.

the more I got into it the more sorry I felt for the perpetrators

When I first got caught up in the SSRI debacle I felt so sorry for the victims — people that were murdered or committed suicide. But the more I got into it the more sorry I felt for the perpetrators. So many of them were so young. Ben Garris was a young boy at the age of 15 who took Zoloft and it made him suicidal so they placed him in a prestigious hospital, Shepherd Pratt, and switched him to Prozac. He told them that he felt violent and they wrote in the hospital notes that he felt violent but they said he was being manipulative. He told me in his letter that he also told them to protect the other patients because he felt so violent. But they didn’t write that in the notes. Anyway he ended up killing a nurse who was on duty there. He got life in prison without the possibility of parole. So he was 16 when he went to prison and he’ll be there until he dies.

And there was a 13-year-old girl in Iowa who killed her great aunt. Stabbed her to death. She was on Prozac. She was given life in prison and the reason I knew it was that my sister sent me the article from the Des Moines Register that said she was on Prozac and that she was the youngest person to be sentenced to life in prison in Iowa. These are just some of the cases of the children.

DH:          Have you had any help from any group or anyone?

RM:          When I first started thinking about setting up SSRI Stories on the Internet, I sent a prototype of the way SSRI Stories would look to Sara Bostock who had lost her beautiful talented daughter to a Paxil-induced suicide. Sara believed that the prototype needed to have a “movable database,” and she hired a computer person to fix the prototype. She also paid for the server for over five years and helped me by posting 200 of the stories that I had saved in my computer. She even invented the name “SSRI Stories.” She believed in SSRI Stories and this gave me the energy I needed to carry out the work on the website. So SSRI Stories owes a lot to her and also to Ann Tracy for her early work.

But, no, other than these two people and my husband being my technician, nobody has come forward to help. There are other people doing a lot of work on psychotropic drugs but they are worn out themselves keeping different sites going. One person did write to me offering to help but I don’t know anyone who can keep up with SSRI stories because of changes in Google.

I don’t know anyone who can keep up with SSRI stories because of changes in Google

For years I went into Google and it said up above images, “Google News,” etc. I would click on Google News Advanced Search. Then when I clicked on Google News I would type in the word “antidepressant” and for that day it would say, for example, March 1, 2010, two hours ago something about an antidepressant that maybe killed somebody. I would quickly scan that to see if it was one of our cases. Then that would say four hours ago, six hours ago, and I could do that day till I was done with that day. I would type in “antidepressant” and “antidepressants,” and “anti-depressant” and “anti-depressants,” and I could get it all for that day. Then I’d type in “medication plus depression,” then I’d type in “medication plus depressed,” and “medication,” and so on. And I’d type in Prozac, Zoloft, Paxil, Celexa — there were nine of them I typed in — and they would come up one hour ago, three hours ago from all over the world. That was what was amazing.

Now when you go to Google news and type in the word “antidepressant” it will come up first of all with Wikipedia. Then it will say four days ago, then two days ago, then six hours ago — it’s 18 times as much work. With just one person trying to do it and then getting sick, it’s got to be too much. Before I was sick, when they changed that, I went ahead and set up a Google alert. Do you know what Google alerts are? I would type in “antidepressant plus murder” and I would type in my email address and have them send me a Google alert for “antidepressant + murder.” That’s an email that they sent to me personally. I was able to work off that for about eight months. I would probably get about 75 of those a day, most of them didn’t have anything to do with antidepressants plus murder. They’d say someone was murdered back in 1910 or something but too bad they didn’t have antidepressants then.

I would have to go through a lot of those that said nothing but then all of a sudden I would come across one that did — that’s how I came across the case of the schoolteacher who was acquitted of molesting a minor male student because of her Effexor usage. After that I typed into Google “Effexor + teacher,” “Prozac + teacher,” “Celexa + teacher,” etc. Then I’d get into a lot of things like a teacher says Effexor is a great drug for whatever.

DH:          How old were you when you created SSRI stories?

RM:          Well I’m 74 now, and I put up my first 1000 cases that I’d saved for 10 years in 2006 — so I was 69. I was in good health then.

DH:          What did you work at?

RM:          I was a music teacher. I went to Catholic University of America in Washington and then transferred to Drake University and got my bachelor of music education in Iowa. I taught for three years and then moved to Omaha where I met Gene. We got married and moved to Houston, Texas. He worked on the moon shot back in 1963, 1964. We lived there till 1968 and then we moved to Dallas. I got in touch with Andy Vickery of Houston over the Sargeant Steven Christian case here in Dallas. So I knew Andy Vickery and Rick Ewing before I even put up my message board.

DH:          You’re a former music teacher who at the age of 69 creates SSRI stories. What could other people do to make a difference?

RM:          Well I think other people should be watching the personalities of people.

watch the personalities of people.

If they see a sudden change in the personality of somebody they’ve known for years they need to ask them “Are you on a medication?” If you ask a person “Are you taking a drug?” they often think you mean an illegal drug. So it’s a very delicate question to ask. I think when a family has a person who starts on a medication and their personality changes, they don’t realize it is the medication causing this. They just think that the illness is getting worse.

We have so many cases where, “Well, he started on Prozac and his illness was getting worse so we took him to the doctors and he doubled the dose.”

We have all kinds of cases like that. So I think people need to be aware of what SSRIs can do and how they can cause this personality change.

DH:          What you’re answering though is what we need to do about this group of drugs. What I’m asking is what can people do to change the system? You’ve been an extraordinary example to people of what they could be doing.

RM:          I wish that there was a group working on the SSRIs because it’s affecting so many people — perhaps as many as one out of three. There is a WEB MD article on SSRI Stories that states that one out of three people may become worse on antidepressants and even become bipolar. I mean in some the effects are just mild personality changes, they get kind of grumpy you know. But there are ones that are serious, I don’t know how often that happens, but it’s a lot.

Another thing is that the suicide rate has not really gone down in the United States. It declined a little in the 1990’s because of the good economy but the government statistics from the years 2005 to 2007 shows it’s gone up for all ages except 24 — the Black Box warning worked!

 terrible things are happening

And terrible things are happening to these poor wounded warriors in Iraq and Afghanistan. They’re giving these kids antidepressants and sending them out in battle where they’re committing suicides and homicides and everything. That man from Sherman, Texas, that went into the clinic in Bagdad and shot five people dead. Remember that one? He was on PTSD drugs, one of them an antidepressant, and they had just changed his dosage the day before. Also, what was the psychiatrist taking who shot and killed 14 American soldiers at Ford Hood, Texas? They did mention in Gulf News that he was the type of psychiatrist who tended to medicate himself.

Some of the atypical antipsychotics like Seroquel and Risperdal can also cause violence and that should be brought out too. And then there’s Chantix, which has so many cases of violence. How many people are taking Chantix? Probably not very many. It’s just for people who want to quit smoking. One person did say to me, and it was a doctor, that yes Prozac is number two on the list in that recent article by Tom Moore, but everybody takes Prozac. In other words he was thinking because of the number of people, there isn’t really a problem. I said well what about Chantix, and he just nodded in a puzzled fashion. Physicians tend to be skeptical.

DH:          Why?

The physician does not recognize what’s happening

RM:          This is what I’ve noticed from the people who have contacted me through SSRI stories. The physician does not recognize what’s happening. The patient is started on Prozac. They go to the physician and the physician says, “How are you feeling?” “Oh I feel tremendous, I feel great.” That’s wonderful, but what’s happening then is that person is going home and they are deviant, they’re divorcing their husband or wife and they’re taking off on a motorcycle — I’m not kidding this is a true story — to go to Florida and live with some beach bum who tends bar. They’re leaving their two children behind and their husband and the doctor didn’t have a clue. Because they said they felt great. That’s what’s so weird.

A lot of people type in “SSRIs and divorce.” I’m amazed the number of people who do that, or “Zoloft ruined my marriage” — I can remember that from many people. Somebody else typed in something like “Paxil made me crazy.” Those are the people who are reaching SSRI Stories, but who are they? They’re just the man in the street and not any powerful group. So we need a group to work on all of these different angles, the divorce, the hypomania, the pyromania, the kleptomania, nymphomania — I think that’s what’s happening to these woman schoolteachers. What they don’t realize is that people who go into mania and hypomania have an increased libido.

It’s the children that disturb me the most.

But it’s the children that disturb me the most. There is a post on SSRI Stories about a 15-year-old girl who was forced by her father to take Paxil and then to double the dose. A few days later she slit her younger brother’s throat and buried him in the back garden. I cannot imagine a young girl doing this. These are some of the really tragic cases and they are being hidden.

This why I can’t read mystery stories anymore. If I wanted to read something, I will read a comedy. Every time Gene and I went to the movies or out with friends to movies we would go to comedies. I would have to see a comedy because I would sit all day long and find those cases and I needed relief from this. All I can say is that we need some group that’s big and powerful who will pick up all the different angles there are in SSRI Stories.

Mystery in Leeds

Sherlock-Holmes

In my blog post The best bias that money can buy I outlined how doing trials of their drugs in conditions like depression is the ultimate way companies hide bodies. That what is needed instead are studies of drugs in healthy volunteers.

Here’s a good example of what a healthy volunteer (phase 1) study can show, and how the story of antidepressants and suicide might have unfolded in an entirely different manner had this study been in the public domain.

How might the story of antidepressants and suicide unfolded had this Zoloft study by Dr. Hindmarch been in the public domain?

In early 1983, almost a decade before it launched in the US, a study of Zoloft (sertraline) was run by Dr. Ian Hindmarch in Leeds, UK. There were 12 female volunteers aged between 34 and 40, drawn from the control panel in the Department of Psychology in Leeds University. The study was supposed to randomize half its subjects to sertraline and half to placebo for a week followed by a cross-over between drugs. It was abandoned before the first week was out.

The medical report to Pfizer noted that the side effects reported in the study were all elicited independently, without communication between participants, that there was a clearcut difference in side effect reporting between placebo and sertraline, and that the volunteers on sertraline were experiencing marked discomfort. The study was accordingly terminated.

All of the sertraline subjects had problems, as had one of the placebo subjects. The placebo subject having problems, however, had sertraline levels in her blood, making the finding even more convincing. The side effects that seemed most clearly linked to sertraline were apprehension, insomnia, movement disorders, and tremors. There were wonderful descriptions of akathisia – the mechanism later linked to suicide induction on SSRIs.

The side effects that seemed most clearly linked to sertraline were apprehension, insomnia, movement disorders, and tremors.

The report to Pfizer noted that these side effects had been described previously by subjects on SSRIs (such as Zelmid, Luvox, and Celexa), that they were well known to be linked to SSRIs, and that as such these effects in this study were likely to be due to serotonin reuptake inhibition.

The volunteers kept diaries in which they reported clear behavioral effects consistent with the warnings that were put on sertraline and other SSRIs 21 years later (in 2004) for agitation and suicidality, as well as a range of other interesting effects.

The Hindmarch study was never published. I got to hear about it in 1998 from Ian Hindmarch himself when we were chatting about an article in the New Yorker by Andrew Solomon that compared the agitating effects of Zoloft to drinking 55 cups of black coffee. Hindmarch said he’d been involved in a study that mapped onto just what Solomon was describing.

Perhaps of considerable importance, despite the outcome of this study, Hindmarch later did another study of Zoloft in healthy volunteers in Leeds that was published in which the volunteers got a much lower single dose of Zoloft.  If anyone tries to find a Hindmarch study of Zoloft in volunteers, they will find this one whose report seems completely innocuous.

If anyone tries to find a Hindmarch study of Zoloft in volunteers, they will find this one whose report seems completely innocuous.

Shortly after our conversation, I came upon Hindmarch’s first Leeds study when I was in Pfizer’s archives in New York acting as an expert witness in a case taken by the parents of Matt Miller. 

Matt Miller was a 13-year-old boy who committed suicide a week after going on Zoloft. Quite extraordinarily, Pfizer argued that this was not suicide but auto-erotic asphyxiation gone wrong. Pfizer recruited Hindmarch as an expert witness in the case. In a pre-trial hearing, he said that nothing much had happened in his healthy volunteer study in Leeds – that the volunteers had been suggestible, as evidenced by the woman on placebo having side effects.

Hindmarch said that nothing much had happened in his healthy volunteer study in Leeds  that the volunteers had been suggestible, as evidenced by the woman on placebo having side effects.

I tried to get the MHRA (the British regulator) to review the study, but am confident to this day they have not seen what I had seen. The correspondence was published on Charles Medawar’s Social Audit website at one point. Journalists applied under the Freedom of Information Act for the study and four years later got a version stripped of its most interesting details.

There are a few points worth noting. Blinding and randomization perhaps make this study more powerful, but the effects were Evident – see False friends.  A controlled trial was not needed to show SSRIs can cause suicide, homicide, sexual dysfunction, and other effects. Pfizer monitors didn’t think they needed to test these findings for statistical significance before deciding what was happening.

Here, many years before these drugs triggered tens of thousands of suicides and acts of violence, was a great deal of evidence outlining the nature of the problem. It still sits in Pfizer’s archives.

Here, many years before these drugs triggered tens of thousands of suicides and acts of violence, was a great deal of evidence outlining the nature of the problem and their understanding of it.

It still sits in Pfizer’s archives.

There were other healthy volunteer trials of Zoloft and other SSRIs in which every single volunteer dropped out – with FDA reviewers aware of this but explaining it away.  In a study of another SSRI one of the most distinguished psychopharmacologists in the world at the time stated he had never seen effects like this after a psychotropic drug was given to volunteers and strongly recommended against the drug being developed further. Many of these studies have correspondence that should see the light of day. In a Cymbalta healthy volunteer study, Traci Johnson committed suicide. At least one other volunteer has committed suicide. Other volunteers have become aggressive.  None of this has happened on placebo.

The seven women in Leeds who got Zoloft may not know to this day what they had or that they are at greater risk of comparable reactions from an SSRI than others. These women are likely to have many more experiences than they committed to their diaries. What did they notice when they got into bed at night?  Have any gone on to commit suicide? It is quite possible that becoming agitated in this way has put each of these volunteers at greater risk of suicide.

Social media are reputed to all but bring people back from the dead.  If alive, the women would be between 61 and 69. They may be living near Leeds still.

There are almost certainly others from other studies with stories worth hearing. But there is a bias that even social media cannot overcome – those who were most badly affected if exposed to a further SSRI are more likely to be dead now from suicide or another serious problem.

Maybe this story will resonate with children or partners or friends.

The best bias that money can buy

Randomized controlled trials (RCTs) were adopted by FDA in 1962 following the thalidomide disaster. This was a way to manage the risks posed by potential poisons. If the toxicity from a drug could be shown to overcome to some extent the toxicity stemming from the illness, a risk-benefit ratio would be set up that would warrant taking the risk of giving the poison.

But what happens when both the poison and the disease produce superficially similar problems – when both an antidepressant and depression produce suicidality for instance? In this case there may be almost nothing that can be done to persuade people that it’s the poison and not the disease producing the effect. Even people of goodwill may look and look at the data and still not make the connection, as with the Shepard illusion (demonstrated in my previous post The Spin that no Data can overcome).

In the case of the antidepressants, given the controlled trial data they were faced with, the FDA had little option but to concede that the drugs caused suicide. Despite this and the Black Box warning put on the drugs, many (maybe most) doctors continue to believe that the FDA only did this because of political pressure from groups like the Church of Scientology.

The only reason the problem ultimately showed up in SSRI RCTs was because the SSRIs were so weak they could only be given to people who were at almost no risk of committing suicide. In this group, the increased risk from the drugs became obvious.

Given a slightly different turn of events, it would have been possible to hide the problem forever – using controlled trials to do so. The only reason the problem ultimately showed up in SSRI RCTs was because the SSRIs were so weak they could only be given to people who were at almost no risk of committing suicide. In this group, the increased risk from the drugs became obvious.

Had the SSRIs been as effective as the older tricyclic antidepressants (TCAs), they could have been put into trials of more severely ill patients in which case the risk from the disease would have been greater and might have been greater than the risk from the drugs.

When in clinical trials the risk from the drugs is greater than the risk from the illness, the relative risk is greater than 1.0. For trials of the TCAs or effective antidepressants given to severely depressed patients, it would likely have been less than 1.0 – even for a medication that caused suicide. The fact that the risk from trials was less than 1.0 – that is, less people committed suicide or went on to a suicidal act on antidepressants than on placebo – would have been taken by the field as evidence the drugs didn’t and couldn’t cause suicide (see Healy 2011: Science Rhetoric and Causality).

The field would have been wrong.

We know from meetings as early as the first scientific meetings held to discuss the effects of the first TCA (imipramine) in 1958 that clinicians using it had recognized it could cause suicide. These doctors could still believe the evidence of their own eyes; they were not inhibited by clinical trial data the way doctors are now.

With the benefit of hindsight we can see what has happened in the case of antidepressants and suicide. How many of these problems have been hidden from view by RCTs?

The broader message though is this: RCTs in principle cannot solve the problem of whether a drug causes an injury or not. They may in fact contribute to answering the question, but if they do, it will be as much by accident as design. In the case of the antidepressants, it was by accident.

With the benefit of hindsight we can see what has happened in the case of antidepressants and suicide, and could design an RCT to confirm the risks from the treatment. But what happens in the case of other problems that might also stem from an illness, where we do not have the benefit of hindsight? How many of these problems have been hidden from view by RCTs?

There are two ways out of this bind. One is to get back to referring to drugs as poisons. We have no difficulties in recognizing the poisonous effects of illegal or over-the-counter drugs, and great difficulties in believing they could be beneficial. This is just the opposite bias. This is exactly the perspective we need to bring to today’s prescription drugs, about which we often know much less than we know about yesterday’s prescription drugs (now over-the-counter or illegal). Prescription drugs are prescription-only because they are riskier than other drugs, not because they are safer.

The other option is to run RCTs of the drugs. Isn’t this what we do at the moment?

No.

The drug-induced agitation may be much more severe than illness-related agitation, but companies will just present the frequencies of both, stripped of their severity codes, and the numbers will conceal the problem.

At present our RCTs are of drugs used for an illness – or rather for a marketing indication. The illness backdrop hides all problems. Almost anything happening on the drug can be filed under the same codes as something happening in the illness. In depression, the drug may induce agitation; the illness does too. The drug-induced agitation may be much more severe than illness-related agitation, but companies will just present the frequencies of both, stripped of their severity codes, and the numbers will conceal the problem.

Worse again, the drug may prove marginally superior to placebo, perhaps only on a rating scale which shows a benefit because of a side effect – a sedative or anxiolytic effect – but this marginal benefit is taken as demonstrating the drug works and doctors are left with no evidence base for practicing the art of medicine – that is deciding when it would be best not to treat with an active agent.

If we want to design an RCT to reveal the effects of the drugs, the first step would be to run them in healthy volunteers. This would make it much easier to spot poisoning.

The immediate response of many to this will be that that would be unethical. Giving potential poisons to people who do not stand to benefit would not be right. Curiously, this mirrors the ethical dilemmas posed by the first RCT in tuberculosis patients where the concern was about whether it was ethical to give placebos to people who needed treatment.

Far from being well-designed or informative, as one might expect in such an ethically fraught situation, phase 1 studies are the most corrupt in medicine. 

In fact companies do healthy volunteer trials. These are called phase 1 trials. Far from being well-designed or informative, as one might expect in such an ethically fraught situation, these studies are the most corrupt in medicine. An industry has been created that takes poor people or students in need of money and pays them to be guinea pigs in such trials.

The trials are designed solely to suit company purposes, such as looking at the half-life of the drug, rather than designed to shed light on the range of things a drug might actually be doing. The data from these studies is never released, and the non-publication rate in these trials is much greater than the non-publication rate in clinical trials – which approaches 50% in some cases. Finally, where clinical trials in patients are registered these days, healthy volunteer trials are not – so no one knows what’s going on. Without access to these studies it is close to impossible to practice medicine – doctors just become conduits for distribution of drugs.

See Healy 2010 – Stress Syndromes.

Press release: Pharmageddon is here


For immediate release
Toronto, February 28, 2012. Pharmaceutical companies have hijacked healthcare in America, and the results are life-threatening.In his new book, Pharmageddon, Dr. David Healy documents a riveting and terrifying story that affects us all. Healy also has an idea for the solution…

 

“A medical classic the day it was published.”
“Pharmageddon is a must-read for anyone in the healthcare world and anyone who plans to need healthcare in the future — in short, everyone.” — Amazon review

 

Dr. Healy’s new book, Pharmageddon, is the story of a tragedy. Key messages in the book include:

US life expectancy drops

Reversing the trend of the past century, life expectancy in the US has already dropped compared to other advanced countries. “We are in a world where increasingly we need protection from the latest miracle cure to ensure we do not die prematurely,” says Dr. Healy.

Lifestyle drugs dominate

The global market for pharmaceuticals is US$900 billion, but apart from cancer drugs, few new drugs target disease.  The bestsellers are “lifestyle” or “risk management” drugs: antidepressants and other psychotropic drugs ($60 billion), cholesterol-lowering statins ($34 billion), blood sugar-lowering hypoglycemics ($24 billion), acid reflux drugs ($26 billion), and treatments for osteoporosis and sexual ”dysfunction.”

Drugs are approved based on incomplete data, and the human consequences are severe

Drug side effects range from discomfort through emotional problems to death. Only 1 in 7 new drugs are superior to existing ones. Not realizing this, millions take the 6 in 7 drugs that aren’t, even though they have not been properly tested for risks of harm, often with grave consequences. At least 1.5 million US hospitalizations a year and about 129,000 hospital deaths are caused by serious drug reactions. Yet, fewer than 5% of serious side effects are even reported. Adverse side effects reported by patients and doctors are discounted as “anecdotal”.  As a result many are dying unnecessarily from heart attacks, suicide, homicide and strokes.

The financial burden of drug effects is enormous

Health care costs are running dangerously high — close to 20% of US GDP — threatening to derail both the US and the global economy.  Drugs are one of the biggest drivers of these costs, directly accounting for up to 20% of health insurers’ costs.   The direct costs of treating adverse drug events are estimated to be US $5 billion per year, with US $100 billion in indirect costs.  Adverse drug events are currently the fourth leading cause of death in the US and Europe and the leading cause of death within the mental health domain.  “This is where any ideas of universal health care will founder,” says Dr. Healy.

Stockholm syndrome: Doctors are being held captive by drug companies

How did the drug companies capture our doctors and medical care?  Dr. Healy draws back the curtain to expose the secrets that enable them to circumvent protections, such as controlled trials, evidence-based medicine, and regulatory approvals.  He reveals the role of medical ghostwriters in supporting “off-label” prescribing and criticizes organized medicine for failing patients. Dr. Healy also demonstrates how statistics are manipulated to hide unwanted outcomes and inconvenient deaths.

What can be done?

Dr. Healy looks at the larger issues that have shaped the current sickness infecting health care and how we might come to grips with and treat this severe disorder.

What he also offers is a solution — RxISK.org, the first free website (not sponsored by big pharma or advertising) for patients and their doctors to research, and more importantly, easily report drug side effects. The website will also offer patients a medical timeline chart that captures essential information on their symptoms that will enable them to have a more informed discussion with their doctors about the prescription drugs they are taking and their possible consequences.

Dr. Healy will be in North America March 4-24 (New York, Toronto, Los Angeles), lecturing at medical schools, and promoting Pharmageddon and RxISK.org.

ABOUT THE AUTHOR

Dr. David Healy studied medicine in Dublin and Cambridge England. Currently a Professor of Psychological Medicine at the University of Wales, he is the author of 16 books, including The Antidepressant Era, The Creation of Psychopharmacology, The Psychopharmacologists Volumes 1-3, and Let Them Eat Prozac.

Dr. Healy is a founder and Chief Executive Officer of Data Based Medicine Limited, which operates through its website, RxISK.org, dedicated to “making medicines safer for all of us” through online direct-patient reporting of drug effects. He also publishes through his blog DavidHealy.org and on Twitter @DrDavidHealy.

PUBLISHER

University of California Press

CONTACT

Please contact us if you would like a copy of PHARMAGEDDON for review purposes, or if you would like to schedule an interview with Dr. Healy.

PHARMAGEDDON
(646) 875-8931
Pharmageddon@RxISK.org

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The Spin that no Data can overcome

Tables

Roger Shepard’s above illustration shows two tables of exactly the same size and shape. It’s an extraordinary example of how even when you know that the table tops are the same, the data changes nothing. The dynamics of perspective mean we continue to see things in the wrong way.

Early on in the Prozac and Suicide controversy, Eli Lilly adopted a strategy that has “put things in perspective” ever since – they asked us to blame the disease rather than the drug. This has framed how we see things since in quite astonishing ways.

While ghostwriting an article on Paxil for GlaxoSmithKline, Sally Laden, perhaps the famous ghostwriter of all, referred to some studies as providing data that no spin could overcome (despite her best efforts to do so). As a tribute to her, it seems a good idea to draw attention to the Spin that no Data can overcome.

When something goes wrong on a drug, it can be difficult to decide if it is the drug or the disease. It is all too easy for drug companies to portray depression as giving rise to suicidality.

When an engine falls off a plane or the plane falls out of the sky, we can spot something that shouldn’t be happening. When something goes wrong on a drug, it can be difficult to decide if it is the drug or the disease. If a drug for weight loss such as fenfluramine causes valvular heart disease, it’s difficult to argue that obesity causes valvular heart disease. But at the opposite extreme it is all too easy for drug companies to portray depression as giving rise to suicidality.

In between lies an area that companies have been busy colonizing ever since Lilly introduced the disease defence, and with time it’s become easier and easier for them to argue that there is some disease somewhere that has caused whatever problems might have been linked to their drug; we have been told schizophrenia causes diabetes among other things.

One way to reframe the issues would be to restore the word “poison” to our vocabulary. Every drug, as one of the fathers of medicine, Paracelsus, said, is a poison, and the art of medicine lies in finding the right dose. This is one of the most famous and hallowed definitions of medical practice but it has become close to illegal to voice it.

Every drug is a poison, and the art of medicine lies in finding the right dose.

In expert reports on drug-induced injury cases, when I refer to all drugs being poisons, the defense lawyers file a motion to have the term poison removed as prejudicial and the judge will commonly rule in their favour. I’m waiting for the argument that it’s unconstitutional to refer to any medicine as a poison.

The bias introduced by a disease perspective unbalanced by a poison perspective is extraordinary. In the case of the antidepressants, the bias is almost complete.  There are studies in which healthy volunteers have become suicidal or committed suicide on antidepressants – and the response from companies and their experts is that these volunteers must have been depressed or bipolar.

After the Black Box warning made it more difficult to blame depression, the antidepressants-causing-suicide story was reframed as an error in diagnosis; these patients in fact had a different disease – bipolar disorder – and if they had only been given a mood-stabilizer rather than an antidepressant, all would have been well.

This story has worked a treat – even though in bipolar patients, anticonvulsants given as mood-stabilizers double the rate of suicides and suicidal acts compared to placebo. It works even though people with epilepsy or migraine given these drugs have double the rate of suicidal acts on them compared to placebo. It works even though healthy volunteers become suicidal on them.

Doctors and academics cannot bring themselves to see medicines as poisons to be used with care. Instead, the disease as the unique source of toxicity frames our view of events.

Despite this, doctors and academics cannot bring themselves to see medicines as poisons to be used with care. Instead, the disease has become the unique source of toxicity and this frames our current view of events.

The role of the disease as a source of toxicity has huge implications for randomized controlled trials, widely trumpeted as the gold standard method of evaluation.

The failure of doctors to spot drug toxicity has huge implications for the continuing existence of medicine as a profession.

We will explore these in my next blog posts.

False friends

‘Evidence’ is what the French call a false friend. You think you understand the word but you don’t. In French or Dutch, the Evidence in Evidence Based Medicine means that something is self-evident – as in using a parachute when jumping from a plane or penicillin for septicemia or an antipsychotic to tranquilize. You don’t need a clinical trial to work out what the right thing to do is or to prove what has happened.

What you see is what you get.

In English, the Evidence in Evidence Based Medicine (EBM) means something that needs proof. If it has to be proven, then it’s not evident. When your doctor practises according to EBM, you are usually being asked to take something that is not obviously good for you. Even if the evidence is provided by completely independent sources there is still considerable scope for experts to get things wrong.

But in the case of EBM most of the evidence is produced by pharmaceutical companies who have as many tricks to maximize the positives as they have tricks to minimize the negatives (as outlined in recent blog posts). Where once we might have put our Trust in Evidence, now we are being Trussed in Evidence (see Pharmageddon).

Under the influence of EBM, the English use of the word is spreading, which plays right into drug company hands. They increasingly manage to get doctors to get patients to jump out of planes with little more than a few ghostwritten articles to bear them up.

There is a lot at stake.

It is this gap that charlatans and quacks exploit.

There is no doubt that doctors and patients can get the evidence of their own eyes badly wrong. Both are biased to seeing cures and hope where either none exists or the improvements have come about naturally. It is this gap that charlatans and quacks exploit.

Randomized controlled trials (RCTs) were designed to save us from the exploitation of charlatans or the false hope of the naïve. They did this originally by showing that patent medicines or other panaceas didn’t in fact work. They were designed to buttress skepticism.

Using trials to keep drugs that don’t work off the market would be a way to promote safety but this is not what trials are used for.

When it comes to the things that count, RCTs are not the gold standard.

Clinical trials have been turned inside out and have now become the primary mechanism by which treatments with minimal or no effects are trumpeted as working.  They have become a means to prevent us from believing the evidence of our own eyes. They are inducing a psychosis.

And far from making us safer, RCTs compromise our safety because trials as we use them now have never been a good way to establish safety, as this series of Spin & Data blog posts will bring out. When it comes to the things that count, such as discovering obvious benefits or hazards to a treatment, RCTs are not the gold standard.

Consider this: When we get access to the data from trials we find that SSRIs or related drugs have about the same effects for primary care nerves as clinical trials for opiates, benzodiazepines, stimulants, or nicotine have shown and could doubtless be shown for alcohol.

Imagine giving nicotine or alcohol as a matter of public policy.

Imagine on the basis of 6-to-8-week-long trials, we were to let companies heavily promote nicotine or alcohol as antidepressants – almost to the point of making it public policy that they be used widely. And certainly having their use written into treatment guidelines that make life a lot more difficult for doctors who might have doubts about the wisdom of treatments like this being given for months or years.

What would we find? That many people would apparently recover on nicotine and alcohol and be able to stop after a few months of treatment. Some patients and doctors would swear by the benefits. Any critics of treatment who said the effects were all in the mind (just placebo effects), would be dismissed as plain wrong. Anyone who has a glass of wine knows that it self-evidently has very real effects. And in the French sense of Evidence, the doctors and patients would be right and the critics wrong. But in this case both doctors and patients would know the pitfalls of both French and English Evidence.

Many others wouldn’t do well. Some others would do reasonably well but would not be able to stop. They would feel more anxious when they tried, and their problems would be relieved by going back on treatment, attributed by doctors to their illness: “Think of it this way, you have the equivalent of diabetes and you have to continue taking the pills.”

We would find an increased rate of birth defects and other complications when these treatments were used by women of child-bearing years. Academics would say that leaving these nervous problems untreated causes birth defects.

We would find an increased rate of suicides – academics would blame these on the illness.

The long-term RCTs of alcohol and nicotine have never been done.

When given for years or even decades, who knows what we would find. The long-term studies of alcohol and nicotine have never been done. The English kind of Evidence just isn’t there.

Is this a fanciful comparison? We have no way of knowing. If the risks are as bad on antidepressants as they are for alcohol or nicotine, it might still be worth taking these risks for severe mood or anxiety disorders. The benefits of the original antidepressants for melancholia, or antipsychotics for acute psychoses or manic states, for instance, were Evident; they were not discovered in or proven by controlled trials. The trial evidence we have amassed since has in fact obscured rather than revealed the Evident, just as trials for alcohol or nicotine or stimulants would obscure rather than reveal the obvious effects of these drugs for primary care nerves.

Either way people should be aware of what we do and what we don’t know. They should know that in most cases these drugs are not self-evidently a good thing. They should be told they are likely to be at least as risky as alcohol, nicotine, stimulants, benzodiazepines, and opiates. Used wisely, an evident benefit can be helpful, but a blind adherence to evidence is not wise.

We throw caution to the winds, almost to the point of jumping out of planes without a parachute – how else to explain giving these drugs to children?

Faced with a doctor persuading them to take alcohol or nicotine for their depression on the basis of Evidence in the English sense of the word, most people would be appropriately cautious because of their familiarity with the Evidence in the French sense of the word for these drugs. But when it comes to SSRIs, we throw caution to the winds, almost to the point of jumping out of planes without a parachute – how else to explain giving these drugs to children?

This was the basis for constructing the Data Based Medicine (DBM) papers on antidepressants – see Call for Papers. These are a mixture of Evidence Based Medicine (French) and Evidence Based Medicine (English).

As for RCTs, these are wonderful when used to eliminate treatments that don’t work or have minimal effects. Used for any other purpose they are the ultimate way for drug companies to hide bodies, as the next blog posts will bring out.

Just as problematic, RCTs are a way to snare anyone concerned about overmedication into disputes about just how many angels there are on the head of that pin. A battle that the critics typically lose in the public domain at least because people who have had a glass of wine have Evidence they feel comfortable with.

Petra’s story

This piece is the first of a series showing people struggling with the Kafkka-esque absurdities of modern healthcare. It is written anonymously. If you’d like to share your story, you can do so on the Share Your Story page.  — David Healy


 

A little over two years ago my daughter’s partner was killed in a tragic accident while in the company of my son. Naturally, this caused terrible grief and sadness for both families. Our family doctor counseled Petra to immerse herself in her work, read, walk, and be assured that time would gradually soften her pain. He prescribed some sleeping pills to help her get to sleep.

Petra went back to work after a week or so but was frequently unable to face it, and after struggling for a month or so took extended leave. Some three months later she saw another doctor at the same clinic who declared that Petra had Depression for which she prescribed an anti-depressant, Cymbalta.

Her doctor explained that her brain was not releasing enough of the chemicals that prevent depression.

Petra said that the drug made her feel sick but that her doctor had told her this would pass. Her doctor had explained that her brain was not releasing enough of the chemicals that prevent depression, and that the anti-depressant would prompt her brain to release more of these chemicals — after a while, her brain would resume releasing the right amounts.

This sounded plausible, if ambitious to me, but I was a little concerned at the nausea and read the notes that came bundled with the drug. Worried by the long list of possible side effects, some of them serious, I called the enquiries number on the leaflet and asked how likely these side effects might be. The very polite receptionist took my number and dutifully called back with the explanation that these things only had to be reported once and they could appear on the list and so the chances of most of the bad effects was close to nil. This satisfied my request and I thought no more about it for weeks.

Also troubling was the existence of self-help sites and forums for people who had problems getting off these medications.

Petra showed no improvement, still had bouts of nausea, was sleeping badly, and began smoking heavily, so I started to look for more information. Google searches returned a number of drug information sites that stated briefly that Cymbalta was effective and well-tolerated but other search results on Cymbalta, anti-depressants, and SSRIs hinted at disturbing side effects. A couple of sites seemed overly dramatic and poorly presented but their existence troubled me. Also troubling was the existence of self-help sites and forums for people who had problems getting off these medications. It became apparent that it would be necessary to find some independent authorities and I sought out some government sites. Some of these had information for patients and prescribing information that raised more questions than answers.

I found a link to the UK enquiry into health 2004 ‘The Influence of the Pharmaceutical Industry” and read many of the depositions, questions, and answers. This was detailed and had both sides of what was clearly an argument about Pharmaceutical company influence on the health of nations. The Pharmaceutical company representatives were not very convincing in their submissions.

I raised the issue with my wife, who shouted at me.

Having established in my own mind that there were serious problems with Cymbalta and probably any of the SSRIs I raised the issue with my wife, who shouted at me that

“She has a chemical imbalance in her brain, she needs the medication.” I was completely surprised by this reaction and provided some written material that outlined some of the problems with antidepressants. Jeannette declined to look at any of it. I suggested to my daughter that I had reservations about her medication but she was not interested, pointing out that her doctor would know all about the various medications.

In addition to smoking heavily, Petra’s consumption of alcohol also increased resulting in many unpleasant times for her friends and family. About four months after beginning to take Cymbalta, Petra tried to take her own life, two attempts, a fortnight apart. On both occasions after drinking heavily she took all the tablets she could find, sleeping pills and Cymbalta the first time, sleeping pills, Cymbalta and Benztropine on the second occasion. The Benztropine had been administered to help a dystonia that had developed  on the first trip to hospital and had been provided in an unmarked bag in case the dystonia should recur. Petra later explained that she thought that taking her own life offered a slim hope of finding her beloved David again and afforded a way of escaping the sadness that she felt might never go away.

Naturally these suicide attempts upset me terribly and I feared that the Cymbalta may have contributed to them. The first pharmacist that I asked about Cymbalta cheerfully drew me a diagram of a single neuron with more serotonin recycled into the synaptic gap when Cymbalta was taken. Another pharmacist that I know very well conceded that the only information that she had originated from Eli Lilly and it wouldn’t surprise her if it was overstated or just plain misleading. This was the first supportive comment that I had heard.

 The first doctor wrote me out a script on the basis that I was clearly depressed about the entire situation.

I spoke at length with six local doctors. Three seem thoroughly convinced of the merits of SSRI antidepressants. The first even wrote me out a script for mirtazapine on the basis that I was clearly depressed about the entire situation, from the tragic accident to my daughter’s reaction and treatment. This after being told that I had serious worries about antidepressants.

The second, Petra’s doctor, conceded that the treatment may amount to no more than placebo but cried, “…what else have I got ? Benzos ?”

The third was generally defensive and unwilling to discuss the matter.

Our semi-retired family doctor whom she had seen first was skeptical of the new antidepressants, and doesn’t prescribe them. The remaining two I sought out after getting their names from a psychologist friend. These are doctors who regularly refer patients for psychological input rather than instituting a drug regimen immediately. Surprisingly, one of them confessed that he did not understand the trial data summaries and was simply skeptical by nature and on the basis of past experience.

All of the doctors assured me that the alcohol and sleeping tablets were more likely to blame and that such events were not associated with long-term use of Cymbalta. It was suggested to me that suicide attempts were more likely early in treatment when increased energy made acting on suicidal thoughts more of a possibility before the anti-depressant factor emerged. I didn’t find any of this comforting. Petra maintains that the Cymbalta wasn’t to blame, but I don’t see how she can be sure of this.

I had confidence that the possibility of a Thalidomide issue was a thing of the past.

Before researching the topic, I had imagined that drug companies were mostly interested in finding new medicines and probably modifying existing ones to deliver better health outcomes for society. I understood that this might be expensive and that there would be no knowing when the next break through might occur. New treatments could be expected to be more expensive than older, less effective ones. I further imagined that considerable trouble would be spent ensuring the safety of any new drugs given disasters like Thalidomide. I was quite sure that there would be government agencies testing all new drugs in order to be certain of their efficacy and safety. I had confidence that improvements were being made all the time and the possibility of a Thalidomide issue was a thing of the past.

Given that only safe and effective drugs would be available, I was happy to leave the choice of drug to the doctor, assuming that clinical experience would guide him or her to prescribe the most appropriate treatment for each patient. Clearly this was the view that Petra held. She had also developed a trusting relationship with her doctor and was finding my reservations about her treatment to be offensive.

 I found it incredible that depression and suicide could be side effects of a treatment for depression.

The first and most disturbing thing that I felt was established about Cymbalta and the SSRIs in general was the unacceptable incidence of suicide as a side effect. I found it incredible that depression and suicide could be side effects of a treatment for depression. This would be like a new brake fluid that worked 5% better than existing brake fluid except for the occasional complete brake failure. This has to be a ‘show stopper’ by any measure. The use of statistics from drug trials in an attempt to reduce this fatal flaw to statistical insignificance utterly failed to move me. The question now was how can such an absurd treatment find it’s way into general practice? Could these claims of suicide during drug trials be wrong?

I was appalled to find that actual suicides had occurred during drug trials and were written up in tabular form along with (fewer) suicides on placebo. It seemed possible that depression leads to suicide and the drugs were simply ineffective. But suicides on placebo ‘washout’ shouldn’t be counted as placebo suicides and the fact remains that more suicides happen on the drugs than on placebo. This is much worse than ineffective, this is a problem masquerading as a solution.

This is a problem masquerading as a solution.

Putting aside the suicides, is it possible that a lot of people benefit considerably from the drugs? I felt that this must be the case and that doctors must see a lot of people who feel much better for the treatment. It was at this point that I read Irving Kirsch’s book ‘The Emperor’s New Drugs” and had the surprisingly large placebo effect in mental illness confirmed. This explains how people could genuinely improve on placebo or equally well on a drug that had no therapeutic benefit. Once we factor in the effluxion of time, possible altered circumstances, the fact that a doctor has been consulted, positive reinforcement by the doctor, plus an expectation of cure or improvement by the patient, it becomes impossible to discern the contribution, if any of an active drug. Nevertheless, the combined effect of all these things looks like ‘the drugs work’.

I think this explains to my satisfaction why doctors might think the drugs work; this and all the ghostwritten articles and company experts at conferences.

Petra has now spent months trying to stop Cymbalta. This is another story we weren’t prepared for that we hope to update you about soon.

 

Randomized God

Several controlled clinical trials have recently been reported in which patients with cardiac conditions who were prayed for appeared to do better than those not prayed for (1, 2, 3).

The surprise that prayer seems to do something has to be matched by surprise at the fact that its effects are relatively weak. If we are to build on this, we need to work out are these weak effects mediated through the people praying (Prayers 1), through the prayers used (Prayers 2), or perhaps through those being prayed for? Psychiatry’s efforts in the last century to establish how influence of a non-physical kind might affect health has led to a series of methodological developments that may offer a framework for further studies in this new area.

 The Prayers (P1)

The influence of the Prayers (P1) might be explored by testing whether greater effects are obtained with a pure sample, such as children or monks, rather than with the mixture of believers used by Harris and colleagues (1). Could the weak effects demonstrated by Christian prayers in this study be bettered by Muslim, Jewish, or Hindu prayers?  If they were, could Christians resort to hiring Hindu Prayers (P1) while remaining Christian?

The possibility that crossover effects are a general phenomenon could be tested by seeing whether Jewish patients do better with Muslim Prayers. If this is not the case, trials will be needed to test the relative benefits of Hindu, Muslim, Jewish, and Christian Prayers in designs that would control for the religion of those prayed for.

A further set of issues are opened up by considering what the effects of Prayers by atheists might be. If these were the most effective, what would the effect on the atheists be?  If the experience converted them, this would raise the problem of ensuring a continuity of the most effective Prayers (P1).

To control for background non-specific effects, it will also be necessary to produce both placebo Prayers (P1) and placebo praying.

In any clinical study, the specific effects, attributed in this instance to God, are those seen over and above any background non-specific effects. In many clinical studies, these background effects may contribute a substantially larger proportion of the therapeutic benefit than the specific effect.  In this instance, one might argue that the actions of Providence are more likely to be manifest through the background effects. Does this raise the possibility of a conflict between two sets of divine actions – direct intervention versus providence?

Prayers (P2)

If efforts to demonstrate the efficacy of prayer as an intervention follow the route taken by methodologists attempting to demonstrate the efficacy of psychotherapy, then the Prayers (P2) used will need to be manualised so that they can be delivered in a manner that separates active ingredients from the conviction or enthusiasm of the Prayers (P1).

This would appear to feed directly into longstanding questions about the relative benefits of the more manualised prayer forms found in Catholicism or Orthodox Judaism compared with the more spontaneous approach found in Protestantism or Sufism. There is a host of other subtle interactional issues to do with incense and physical orientation while praying that will also need investigation.

There is fascinatingly some evidence for possible benefits of meditative practices and ritual Prayer as it is (4), which suggests the question as to the most effective type of Prayers (P2) may be a substantial one.

A host of issues follow depending on whether the benefits are ultimately seen to lie in the Prayers said (P2) rather than the Prayers praying (P1). If the benefits lie in the form of Prayers (P2), some form of patent protection might be needed for companies hoping to develop better products. The patenting of Prayers© may seem an extraordinary development but as life is now being patented, the barriers to such developments may not be what they once were.

Governments or religious authorities, however, may wish to make arrangements to take out protections on products already in common use to ensure that the labor of millenia is not lost to the communities who did the work. Universities might consider establishing departments of ethnosupplicantology to research the methods of traditional healers in this sphere, before these get lost with the development of more commercial products.

However, it is also not uncommon when it comes to pharmacotherapy to find that a product with weak or minimal evidence of efficacy dominates the market. The success of the product often owes more to astute marketing rather than the efficacy of the product.

Nevertheless, there is some regulation of marketing claims for drugs. Who will regulate the claims that may be made for any new prayer products?  In this regard, it is of some interest to note the differences between Catholic/Orthodox and Protestant/Hasidic markets, with Catholics for example having, in the case of the Magisterium, a set of arrangements closer to the current pharmacotherapy marketplace than Protestants. Moves toward over-the-counter sales of drug therapies and direct-to-consumer advertising may represent a switch from orthodox toward more reform-minded models.

 The “Sinner?”

Aside from the issues of Prayers (P1) and Prayers (P2), there is also the possibility that the efficacy of prayer may have less to do with a specific intervention or particular therapeutic style than with the state of the individual being prayed for. In this case, presumably the number of “sins” of the ill person would be a crude proxy measure for the relevant aspect of the patient’s condition. This might mean the generation of an appropriate rating scale, perhaps the Prodigal Son Rating Scale. It will be necessary to establish whether any effects occur in proportion to an individual’s history of sin, and  whether there is any specificity in the match between particular sins, prayers, and prayers?

We may have a real therapeutic crisis if it turns out Prayers (P1 or P2) work better for sinners than for the virtuous. This seems a problem because sins from gluttony to alcoholism appear more closely linked to ill-health than does virtue. Who will want to live a good life if a few prayers can take care of the problem?

Theo-therapeutics: Does God play dice? 

In pharmacotherapy, it is commonplace to demonstrate acute treatment effects but there is a growing recognition that in some cases the longer term outcomes may not be as good as the short-term benefit might have suggested. Will there be a need for longer-term outcome studies? Perhaps those who survive as a result of prayer are more likely to regret their survival. Are we assuming that the God prayed to is always benign?

In pharmacotherapy, it is also commonplace to use surrogate markers rather than hard outcome measures, such as mortality statistics. While this new field appears to have commendably begun with the most robust of outcome measures – survival – there will presumably be some scope for the development of surrogate markers, such as rating scales of spirituality to further establish the effects of “treatment.” What would we make of a development in which subjects did not survive longer but did become more “spiritual” as a consequence of prayer?  The elaboration of surrogate markers probably depends to some extent on the degree to which the field becomes commercialized (5).

In the pharmacotherapeutic arena, finally studies that do not support the previously demonstrated efficacy of a compound are not published. In the event that the studies referenced here are not replicated, can we be sure that the data will be published? Given that this is a new area of therapeutic endeavor it might be possible from the start to insist that the data is made available rather than simply registered. Wouild Ghost-writing be as big a problem in this area as pharmacotherapeutics?

If the benefits lie in the Prayers (P2), interesting issues of product liability open up.  If on the other hand, the benefits lie in the individuals praying, the pressure on hospital managements to enlist effective Prayers (P1) would be irresistible. They would presumably also be obliged to ensure that the best match of Prayers (P1) to patients was found, even if this meant the use of non co-religionists. A failure to do so, despite the protests of patients, would presumably leave hospitals legally liable.

In the current climate, hospitals would presumably only wish to appoint accredited prayers. Training programs and re-accreditation would no doubt in due course become points for debate. Would it be possible for religious organizations to run Continuing Supplicantology courses or would this constitute a conflict of interest?

How long will it be before the prospect of  some religious leader being answerable to the spiritual equivalent of a Medical Council rears its head?

On the upside, all this pragmatism might in due course produce both doctrinal progress and religious renewal.  It might also finally answer the question of whether God plays dice.

 References

1). Harris WS, Gowda M, Kolb JW, Strychaz CP, Vacek JL, Jones PG, Forker A, O’Keefe JH, McCallister BD (1999).  A randomized controlled trial of the effects of remote intercessory prayer on outcomes in patients admitted to a coronary care unit.  Arch Intern Med 159, 2273-2278.

2). Byrd RC (1988).  Positive therapeutic effects of intercessory prayer in a coronary care unit population. Southern Medical Journal 81, 826-829.

3). Leibovici L (2001).  Effects of remote, retroactive intercessory prayer on outcomes in patients with bloodstream infection: randomized controlled trial.  British Medical Journal 323, 1450-1451.

4). Bernardi L, Sleight P, Bandinelli G, Cencetti S, Fattorini L, Wdowczyc-Szulc J, Lagi A (2001). Effects of rosary prayer and yoga mantras on autonomic cardiovascular rhythms: a comparative study.  British Medical Journal 323, 1446-1449.

5). Healy D (2012).  Pharmageddon.  U. California Press, Berkeley.

We need data for Data Based Medicine

One of the purposes of this blog is to invite colleagues to add to the knowledge base on drug groups. To submit a paper or to provide your comments, please do so on the form on the Share Your Story page.

I’ll start the ball rolling with the following draft Data Based Medicine (DBM) papers:

We have draft papers in preparation on: Mood Stabilizers, Antipsychotics, Stimulants, Dopamine Agonists, Statins, and Hypoglycemics.

We need papers on: Treatments for Asthma, Hypertension, Osteoporosis, Antibiotics, Anti-Ulcer Drugs, Contraceptives, Analgesics, Anti-inflammatories, Drugs for Sexual Functioning, and others.

Principles underpinning DBM papers

The emphasis is on highlighting missing data. This may be:

  1. Hidden data: data from trials hidden through miscoding, ghostwriting, etc. (see recent posts)
  2. Missing data because of trial design: e.g., flawed design, too short, or surrogate outcomes
  3. Missing data because the right studies have not been done: as in adverse events
  4. Data that is hidden by statistical sleight of hand

The questions used in the current drafts are almost more important than the answers. We want questions that reveal our uncertainties and lacunae in our knowledge rather than questions that falsely reassure. The emphasis is on highlighting the unanswered questions where doctors and patients have poor information on which to make therapeutic judgments.

We encourage anyone writing, editing, or contributing to a paper to resist the temptation to advocate for a treatment, in particular a non-drug treatment, and to resist the temptation to denigrate the use of drugs for what they see as lifestyle or trivial purposes.

The aim is to appraise doctors and patients of the state of the data — in contrast to the state of what is called evidence — and to encourage them to observe previously unreported or poorly documented effects of drugs and to contribute these observations to the pool of data that helps guide decisions.

The aim is to make doctors and patients aware that the current state of the data at best permits guidance to supplement therapeutic judgments and does not mandate guidelines to replace clinical judgment or patient values.

Data Based Medicine believes that controlled trials are extremely important but have come close to being made into a fetish. They are, moreover, probably not the best method to reveal treatment related adverse events (see posts).

Authors are encouraged to return to the original definition of evidence based medicine which was an “integration of the best research evidence with clinical expertise and patient values” (Sackett & Rosenberg 1995).

This will result in papers that will have a judicious mix of best evidence and consensus view that may in some instances have a “return to the 1990s” quality to them.  The best example may be pregnancy and antidepressants: it was so much received wisdom in the 90s that women should avoid drugs in pregnancy that there is almost nothing saying this.  This has left a gap through which companies and other interest groups have been able to march – claiming that all the evidence points to the need to use antidepressants in pregnancy.  Going back to the 90s will mean apparently going against what purports to be evidence.

Justifying such papers will be an interesting  exercise that may need to tap all the resources this approach can mobilize.

David Healy
February 2012

 

Coincidence a fine thing

Coincidence can be a fine thing. No sooner had I finished The tricks that drug companies do live after them, asking for examples of maneuvers to add to a generally available repository of tricks, than up pops Robert Gibbons’ paper, Suicidal Thoughts and Behavior With Antidepressant Treatment, with not one but two maneuvers and reminders of others.‎

Dangerous liaisons

First off, the reminders. Gibbons has previously produced data showing apparent rises in juvenile suicide rates alongside falls in antidepressant prescription rates. This was an ecological fallacy maneuver taken to an extreme.

What is the ecological fallacy?

Well, there was a general fall in suicide rates in the 1990s and 2000s in line with rising antidepressant prescription rates; but claiming there is a link ignores the rising suicide rates that went hand in hand with rising prescription rates for antidepressants in the 1960s and 1970s when these were more likely to be given to suicidal patients and should — if antidepressants help — have made a difference.

But as I’ve argued elsewhere, these data from the 1960s and 1970s should not be taken as evidence that antidepressants cause suicide.

The link between suicide and autopsy rates is much tighter than the link between antidepressant prescriptions and suicide rates.

Why? There are too many intervening steps. In this case autopsy rates are one. These rose as suicide rates rose in the 1960s and 1970s. These fell in the 1980s as suicide rates fell (before SSRIs were launched) and continued to fall in the 1990s and 2000s. If autopsies aren’t done, many suicides (and homicides) are missed. (See Reseland, Le Noury, Aldred, & Healy, Psychotherapy & Psychosomatics, 2008 and a better paper by Kapusta et al 2011 Arch Gen Psychiatry doi:10.1001/archgenpsychiatry.2011.66.) The link between suicide and autopsy rates is much tighter than the link between antidepressant prescriptions and suicide rates.

Cherry picking

Despite this, after the 2004 warnings on antidepressants Dr.Gibbons found one country where he claimed a minor blip in pediatric suicides figures in one year (not replicated the following year) showed the warnings were leading to suicides by putting people off treatment (Gibbons RD et al Am J Psychiatry, 2007, 164, 1356-1363). And he is quoted in the LA Times on 7 February 2012 (Study questions antidepressant link to suicide in kids) as saying, ‘The impact of the ‘black box’ warning…was to reduce antidepressant prescriptions to kids — which was correlated with an increase in suicide rates in subsequent years.”

Gibbons continues to link black box warnings on antidepressants with an increase in children’s suicide rates, even though his 2007 paper was later described in the BMJ as “astonishing,” “misleading,” and “reckless.”

He says this, even though his 2007 paper was later described in the BMJ as “astonishing,” “misleading,” and “reckless,” and one of its researchers, Ron Herings, later said the study’s findings are “not right” and that it “doesn’t follow from the data, it is not true and serves just to scare people. It is hard to admit this, as I am one of the authors of the article and I attached my name to it …”

Fellow researcher Ron Herings later said, “… it is not true and serves just to scare people. It is hard to admit this, as I am one of the authors of the article and I attached my name to it …”

Hard to beat this, you might think, but the latest Gibbons’ study manages to do it.

Republish a discredited approach

In the latest paper, Gibbons uses a drop in scores on item 3, the suicide item, of the Ham-D rating scale in patients on antidepressants that he implies is so substantial a benefit it outweighs any conceivable harms — none of which were detected. On top of this he throws in a lot of largely irrelevant language about statistical modeling and purports to be analyzing a bigger database than the database on which warnings are based.

The first trick is that this study, shorn of irrelevant statistical modeling, had essentially been published in the BMJ 21 years earlier.

The first trick is that this study, shorn of a lot of irrelevant statistical modeling, had essentially been published in the BMJ 21 years earlier in September 1991 by Beasley et al.  FDA used this publication to justify not putting warnings on Prozac in 1991. This was the approach that Lilly took to hide the excess of suicidal acts on Prozac outlined in Drug companies use studies the way a drunk uses a lamppost and Psychotic doubt. ‎

But here’s the rub:

“Item 3 of the Hamilton scale for Depression ratings which provide the data for the analysis is an insensitive measure of suicidality: a rating does not entail the asking of any standard questions and the anchor points for scoring aren’t well defined. Furthermore in interviews characteristic of clinical trials, clinicians noting an improvement in depression will tend by virtue of a halo effect, and the counterintuitive nature of the emergence of suicidality in such circumstances to rate scores down.”

This quote from a 26 October 1991 letter in the BMJ, in response to the Beasley meta-analysis of Prozac and suicide in 1991, is polite academic speak.

What it really says is this:

  • Some of the doctors running clinical trials and doing these ratings are pretty incompetent and just in it for the money.
  • Others are competent but rushed and have their junior doctors or research assistants do the ratings.
  • Others are rushed and fill the rating scale hours (or maybe days) later based on general impressions and a rushed question to which a seriously suicidal patient might well have responded ‘I’m fine doctor’ score the suicide item down.

What I didn’t know then was that in some cases the patients in these studies may not have existed.

Non-existent patients

Non-existent patients are particularly useful in that their rating scales always go the right way and remain obediently hand in hand with their suicide scores: They can’t die, unlike real patients whose ratings might go the right way but who engage in suicidal acts.

Eyes wide shut

To spot patients getting worse you have to be looking for the problem, and these raters weren’t; some possibly suspected they were likely to have been dropped by Lilly or Wyeth if they showed any signs of spotting a problem. But it’s harder to ignore suicidal acts and it was this that ultimately gave rise to FDA’s discomfiture in 2004.

These raters may have suspected they were likely to be dropped by Lilly or Wyeth if they showed any signs of spotting a problem.

While David Graham of FDA also made this argument from early on, it took Tom Laughren (FDA’s point man on the issue) a suspiciously long time to concede in public that “looking at items from the rating scales… turned out not to be very helpful….[This method] did not detect a signal in these trials…and was not particularly productive.”  (February 2, 2004 PDAC, pages 342-343)

How bad can it get?

Well, very bad. At the 2004 hearings, John March, a lead investigator on the TADs study that Gibbons and colleagues say they have incorporated in this paper, defended the use of Prozac for children. This use is defensible but for reasons of profound self-interest doctors should not be party to a defense that involves hiding problems.

For reasons of profound self-interest doctors should not be party to a defense that involves hiding problems.

Göran Hogberg from Stockholm recently tracked down the full data (unpublished) on suicidal acts in the TADs study, which are laid out in Table 1.

Table 1

Treatment

N

Children with a suicidal event

%

Fluoxetine alone

126

27

22

CBT and fluoxetine

107

9

8

All fluoxetine

227

36

16

CBT alone

103

5

5

Placebo

103

3

3

All non fluoxetine

206

8

4

There were two other pediatric suicide trials of Prozac used by Gibbons and colleagues in this paper. These employed maneuvers 7 and 8 from the less commonly listed strategies table in my post The tricks that drug companies do live after them. That is, patients responding to placebo were dropped from one study (7), and patients doing poorly on Prozac were dropped from another (8).

Despite these steps, there was still an excess of suicidal acts on Prozac. Dr Gibbons and colleagues apparently “found no evidence that fluoxetine increased the risk of suicidal thoughts or behavior in youths.”

They can’t have been looking very hard.

Or else the wording is critical – you drown one signal (suicidal acts) with background noise in a more general signal (suicidal ideation).

FDA became party to a myth that somehow Prozac was ok where other antidepressants given to children weren’t.

Because FDA had licensed Prozac for depression before the 2004 suicide controversy blew up, they became party to a myth that somehow Prozac was ok where other antidepressants given to children weren’t. Prozac in fact shows no more efficacy than other antidepressants for children and has just as bad a suicidality profile, along with a range of other harms such as sexual dysfunction, inhibited growth, and other problems, as other antidepressants.

This is not an argument against Prozac. Suicidality can be anticipated and forestalled by warning patients. I once thought that an appeal to patient safety would get doctors on board.

This is not an argument for not using Prozac. As I also mentioned in the 1991 letter to the BMJ:  “The significance of the emergence of suicidality.. is that it can be anticipated and forestalled by warning patients.” I once thought that an appeal to patient safety would get doctors on board – but apparently not.

Professional suicide

The final sentence on Gibbons study in the LA Times is, “I hope that the warnings will not prevent depressed children and adults from getting treatment for depression… The greatest cause of suicide is untreated or undiagnosed depression. It’s very important that this condition be recognized and appropriately treated and not discarded because doctors are afraid to be sued.”

This is a recipe for professional suicide.

If the drugs are wonderfully effective and come with no problems, it would be much less expensive to have non-medical prescribers bring the benefits/salvation that drugs can bring. This is perhaps not the kind of thing Dr Gibbons can be expected to be sensitive to — as he is not a doctor.

If the drugs are wonderfully effective and come with no problems, it would be much less expensive to have non-medical prescribers bring the benefits/salvation that drugs can bring. 

Gibbons ends his article by setting up my next set of posts beautifully when he notes that there are limitations to RCTs when it comes to studying the risk of suicide on antidepressants. There are indeed – but not the ones he suggests.  I will explore some limitations over the next 2 weeks under the heading of Spin & Data.