8.27.2002
Paxil On Trial: The Testimony Of Dr. David Healy, Federal District Court Cheyenne, Wyoming, May 22, 2001, Part I
The marketing life of GlaxoSmithKline's (GSK's) anti-anxiety/depressant drug Paxil is down for the count. Last week, federal district Judge Mariana Pfaelzer in Los Angeles ordered GSK to halt advertisements claiming Paxil is not addictive. The injunction against the advertisements was brought by 35 plaintiff's suing GSK over the marketing of Paxil. Meanwhile, GSK is appealing the ruling and, in what some would characterize as an act of blatant political interference in the case, the Justice Department has sided with GSK, arguing that the Food and Drug Administration says Paxil is not habit forming and only the regulatory agency should have jurisdiction over this issue. So the ads are back on the air for now.
It's worth remembering that last year in a federal district court in Cheyenne, Wyoming, Paxil was found to be primarily responsible for the actions of Donald Schell, a Gillette, Wyoming man who killed his wife, daughter and grand-daughter on February 13, 1998 after only two days on Paxil. The Justice Department didn't intervene in that case and GSK quietly settled its appeal of the case, a major blow for the company. Below is the testimony in the case by British psychiatrist and psychiatric historian Dr. David Healy of the University of Wales. His testimony raises all of the concerns that arise when a private entity like GSK is allowed to fund all clinical testing of its patented drugs and treat the data as proprietary information. Certain topics, like Paxil and suicide, almost never get studied, and when they do, the inconvenient results GSK, or SmithKline Beecham prior the merger with Glaxo, doesn't want the public to see get put on the shelves in the company archives.
If the FDA claims Paxil isn't addictive, then I would like to see the long term studies that prove it. I doubt GSK has adequately studied the topic of Paxil and addiction. If GSK won't study the topic, then who else can we ask about it but the patients who have experienced withdrawal side effects and their doctors? It's interesting to note that Healy found evidence in the GSK archive that the company was aware of possible withdrawal side effects caused by Paxil. The testimony wasn't allowed into evidence because it went beyond the boundaries of the topic at hand, but it sure would be relevant in the matter of whether or not Paxil is addicting.
The work of Dr. Dunner and Dr. Montgomery mentioned below has been outed as company sponsored "ghostwritten" jobs. Dr. Dunner admitted to Sarah Boseley of the Guardian on February 7 that he never saw any of the clinical trial data on Paxil he was purported to have reviewed for a March 1995 European Neuropsychopharmacology article. "Paroxetine" is the generic name for Paxil. "Fluoxoetine" is the generic name for Prozac. "Selective Serotonin Reuptake Inhibitors" refers to a class of psychiatric drugs that includes Celexa, Luvox, Paxil, Prozac, Zoloft.
I will publish Healy's entire testimony in four parts over four days. Today, August 27, will feature the first half of Healy's testimony. August 28 will feature the second half. The cross-examination of Healy will be published in two parts as well on August 29 and 30 respectively. Mr. Vickery is the attorney representing the plaintiff's, while Mr. Pruess is GSK's attorney. -Rick Giombetti
Trial proceedings reconvened 9:00 a.m., May 22, 2001.
MR. VICKERY: We call Dr. David Healy. (Witness sworn.)
MR. PREUSS: Your Honor, before we commence I would like to state for the record an objection based upon the grounds stated in our Daubert motion, are cognizant of the ruling and I would like to reserve my right to examine as part of my normal cross.
THE COURT: Very well. Thank you.
THE CLERK: Please state your name and spell it for the record.
Q.(BY MR. VICKERY) State your name, please, sir.
A. My name is David Healy, D A V I D, H E A L Y.
Q. Okay, sir. When I called you, I said Dr. Healy. Are you in fact a doctor of some sort?
A. I am, yes, Mr. Vickery. I'm a medical doctor. I'm also a consultant psychiatrist and a doctor doctor in the sense of I've got a postgraduate hire degree in this area.
Q. Is that sort of like a Ph.D. in this country?
A. Yes, it is.
Q We can all tell from your accent you're not here, are you?
A. No, I'm Irish, Mr. Vickery and I hope -- well, my accent may cause some problems to the court. I realize the jury can't intervene if my accent is a problem, but I would hope Judge Beaman and perhaps the court reporter would, if anything I say seems unclear, please help me.
Q. I think if you keep your voice up like you're doing now, you'll do just fine. Dr. Healy, how old a gentleman are you?
A. I'm 47, Mr. Vickery.
Q. Where were you born and raised?
A. I was born in Ireland, the north side of Dublin. I was raised there before going to university there. I then went over to the university of Galway to do research and left Galway for England for the University of Cambridge around 1986 and have been in the UK since then.
Q. Did you do your medical degree first or your Ph.D. equivalent first?
A. Well, where people here have an M.D., we do an MB in Europe, usually, and I did my MB first and after that did the Ph.D. work.
Q. Did you then pursue a residency in psychiatry?
A. Yes, I did.
Q. And did you do that after the Ph.D. kind of work or --
A. Yes. After I had done my research and actually during the course of the research, I did the early part of my psychiatric training in Ireland and the later part of the training at the University of Cambridge.
Q. When you were doing the Ph.D. equivalent work, did you have a particular field of interest or study?
A. Yes, I did. My Ph.D. is based largely on the serotonin reuptake mechanism, the mechanism on which drugs like paroxetine work. I also looked at various different serotonin receptors like the serotonin 2 receptor, which is of interest, I think, in terms of the problems that drugs like Paxil can cause.
Q. Let's break it down a minute there. Serotonin -- I know the jury has heard the opening statements and a little bit of testimony from Mr. Haase yesterday about it. But would you just explain for them what serotonin is and how important it is or how it functions in the brain.
A. Serotonin is one of many brain neurotransmitters. There may be up to 100 of these. It is one of the ones that we learned about first. We learned about it first largely because a drug which you will all know well, LSD, acts on this system. It is a system that later in the -- in the early 1970s became of interest to people working in the field of mood disorders. They thought it may be useful to create drugs which acted on this brain system to see would these be useful drugs to treat nervous problems.
Q. When you say neurotransmitter, can you just explain that process? Is that some kind of communication process between cells in the brain?
A. Yes. I mean, that's the easiest way to put it.
Q. And did I understand you to say there may be up to a hundred different chemical neurotransmitters?
A. There may well be, yes.
Q. You mentioned receptors. Would you just explain in real plain terms what a receptor is.
A. Yes, if you think of serotonin as the key, there are a bunch of locks on the other nerve cells, and serotonin can fit into a number of different locks. Now, it will only fit into what are called serotonin locks and there's serotonin 1, serotonin 2, serotonin 3 locks. And there are more, but they're the ones, I think, of interest to us.
Q. You mentioned the 1, 2 and 3. Is serotonin typically writing in scientific literature as 5HT?
A. Yes, Mr. Vickery, that's the way it was really written first of all. The word "serotonin" has largely gained currency thanks to SmithKline Beecham. If SmithKline Beecham hadn't coined the acronym SSRI probably we wouldn't be using the word now today.
Q. Now, I have written here on this sheet of paper 5HT1 and then down below 5HT2. I still can't do that thing right. Is that the way that one writes when they're describing the serotonin 1 or 2 receptor?
A. Yes, it is.
Q. Has anything good in the history of mankind ever happened as a result of some drug impacting the 5HT2 receptor?
A. The drug company and probably the researcher who has looked at this particular receptor the most is a man called Paul Janssen. And you've just slightly paraphrased his quote, which that there's nothing good known to man that comes from serotonin acting on this particular receptor. LSD, for instance, acts on this receptor. Paroxetine makes a large amount of serotonin, excess serotonin, available to this receptor.
Q. And we really kind of got diverted. We were talking about your background and your education. Has any of your research either before you got the Ph.D. equivalent or after, any of your research on the serotonin system in the body been funded by SmithKline Beecham?
A. Yes, a great deal of the research that I did during the 1980s was funded by Beecham as it was then. I was looking at serotonin reuptake and the drug that they had at the time was a drug called miaserin which was a nonserotonin reuptake inhibitor that we have in Europe that you have ever had over here and what I was doing was giving this drug and another drug which was a serotonin reuptake inhibitor to a group of people who were depressed and looking at what changes in the serotonin reuptake system as people get well.
Q. And was that research funded by SmithKline Beecham?
A. Yes, it was.
Q. And you were a clinical investigator for it?
A. Not a clinical investigator, no. I was doing -- what I was doing was we were looking at people going through the psychiatric unit where I trained and any of the people who were actually very severely depressed were the ones we actually recruited to the trial where we gave miaserin, Beecham's drug, and the other drug we were looking at. I have been a clinical trialist for SmithKline Beecham since after I moved to the UK.
MR. VICKERY: Let me ask counsel something.
Q. (BY MR. VICKERY) How many different trials have you conducted for SmithKline Beecham or at least where they funded it?
A. Yes. I've been involved in three different clinical trials. In one of these, it was a clinical trial looking at SmithKline Beecham's drug paroxetine which is the one of interest to us. And we were looking to compare it with another drug called lofepramine which you don't have over here, but the interesting thing with this drug is that it has no actions on the serotonin system at all. We were looking at the two drugs in an elderly group of people who were depressed and we were looking to see which of the two drugs was actually the one that was probably -- perhaps the best drug to use for older people who were depressed.
Q. All right. Of the -- did you say three total?
A. Yes, that's only one. The other one we did then was -- SB as we usually refer to them over in the UK --
Q. They're headquartered over there; is that right?
Yes.
Q. And you're over there?
A. Yes, I am. They had a drug which acts on the serotonin 3 receptor and they had hoped that a drug that would block this brain receptor would be an anxiolytic drug so they ran a clinical trial.
Q. That's a ten penny word. Don't want any ten penny words. What does anxiolytic mean?
A. It means would make people who are anxious less anxious.
Q. Continue telling us about this study.
A. Again, this was a clinical trial that I was involved in for them and it was being used to look at people who were anxious.
Q. And then what was the third trial?
A. The third trial was later on, again, this was probably about 1993, '94, where they were looking to compare paroxetine, Paxil, with a drug called clomipramine to treat people who had OCD which is obsessive-compulsive disorder. And again, we were actually involved as one of the clinical trial centers which recruited people for this particular study.
Q. All right. Dr. Healy, were all of those studies completed? Did you complete all of those studies?
A. Yes, we did.
Q. And did you turn over all of the data that was generated from them to SmithKlineBeecham?
A. Yes, we did.
Q. And was all of that data made publicly available?
A. No, it wasn't. Two of the trials were sealed and have never seen the light of day as far as I know.
Q. Okay, sir. Now, you've told us already you're a psychiatrist. Are you also a neuropsychopharmacologist?
A. Yes, I am, Mr. Vickery. During the early 1990s I was the secretary for the British association for psychopharmacology. During the course of this trial you've heard people refer to the ACNP, an article actually brought out by the ACNP authored by J. John Mann. ACNP stands for the American college of neuropsychopharmacology. In the UK the BAP, which is what I was the secretary of, is the UK version of ACNP here.
Q. Okay, sir. Now, tell me this: In addition to being a psychiatrist and a neuropsychopharmacologist, are you also a historian?
A. Yes, I have been interested in the history of the field for some considerable period now, perhaps since I actually began the research in this area looking at serotonin reuptake and recently, as you will know, authored the only book on the history of the antidepressants which was published by Harvard University Press. I have a further book due out later this year from Harvard University Press called the Creation of Psychopharmacology.
Q. In addition to those do you have a series of three volumes of interviews with the major players in the field of psychopharmacology?
A. Yes. Since about 1993 or thereabouts I've made it my business for research purposes to go around with a tape-recorder to approximately 100 of the leading people in the field, both the people who have made the drugs, the people who have worked with them clinically, the people who have devised the marketing campaigns, people who have won Nobel prizes, the lot and I've interviewed at least 100 of these people. The interviews have been brought out so far in three volumes. There's over a million and a half words and something like 2,000 pages.
Q Back to a moment to your contacts with SmithKline Beecham. Have you ever been asked by them to speak publicly on behalf of Paxil?
A. I have been asked on a number of occasions. When the clinical trial for paroxetine in OCD was done, there was a launch meeting that was held in Nice I guess around '95, '96.
Q. Is that in France?
A. Nice in France, the south of France where they brought clinical people from all over Europe, speakers from the U S to this meeting, and they also brought me to speak on the podium about the issues to do with the treatment of people who had OCD. There's been a further time actually.
Q. I was going to say when is the last time that you spoke at the instance of SmithKline Beecham?
A. I have spoken rather regularly, been asked fairly often over the course of the last nine or so odd years and prior to that during the 1980s in forums in Wales where I work and in forums in the north of England to consultant psychiatrists, G Ps and others on the treatment of people who were depressed with either the SRIs or other drugs.
Q. And, Dr. Healy, how long have you been writing about and speaking publicly in scientific settings about the problem of SSRI-induced suicide or violence?
A. I have been speaking on this issue publicly since about 1991. The most recent lecture I gave was five weeks ago at the university of Toronto. Roughly a year ago I was asked to speak on the issue of antidepressants and suicide by SmithKline Beecham in north Wales, and the interesting thing about this particular lecture was it was made clear to me by the representative from SmithKline Beecham afterwards that they would not be asking me to talk again.
Q. Did you express the opinions in that lecture that you intend today to express in this courtroom?
A. Yes, I did.
Q. Did you use in connection with that lecture some of the slides you have prepared to illustrate your testimony here?
A. Yes, I did.
Q. Are all of the slides you prepared to illustrate your testimony here slides that you have used in numerous professional lectures?
A. Yes, absolutely, to audiences of 1 or 200 or more on regular occasions during the last two or three years. What you will have when we later show these slides are the ones I've been using for roughly the last two years.
Q. You mentioned a minute ago something about SmithKline Beecham coining the term "SSRI"?
A. Yes. It is an interesting little story, I guess. Having got very close contacts with SmithKline Beecham in the early 1980s, I was aware that they had a drug called paroxetine. You have heard only of the story that this emerges in 1988. In actual fact, it was a drug they got from a company called Ferrosan in 1978. Ferrosan at this stage had two drugs which were SSRIs. SmithKline Beecham purchased from Ferrosan the drug that was thought to be the weaker of the two clinically but commercially more interesting in that you only had to give one pill per day.
Q. Let me stop you and make sure we're communicating. This company Ferrosan had two drugs?
A. This company Ferrosan had two SSRIs.
Q. Two SSRIs. And one of them was better clinically?
A. Well, one of them had been made first which was another drug made in 1975. 1978 they make paroxetine.
Q. Are these synthetic drugs. They you say made, is this something they make up in the lab?
A. Yes, they were the ones who actually went through the process of working at what you had to do to a molecule to make it do this thing which was to inhibit serotonin reuptake.
Q. And in what way was the other drug better than paroxetine?
A. The clinical results, the early clinical work they had suggested that it was probably more potent.
Q. When you say clinical work, are you talking about trials with patients?
A. Early clinical trials with patients.
Q. All right. And can you tell us, then, why they chose the one that was less potent?
A. I can't particularly tell you.
MR. PREUSS: Objection, foundation, Your Honor.
THE COURT: Sustained.
Q. (BY MR. VICKERY) Can you kind of skip forward in the story and tell us when and why they coined the term "SSRI"?
A. Yes, I think -- it is quite clear. It is a clear matter of the record that they came to the market after a number of the other drugs which are now called SSRIs, and the marketing department within SmithKline thought that a snappy acronym --
MR. PREUSS: Objection, no foundation, Your Honor.
MR. VICKERY: Let me lay the foundation, if I may.
THE COURT: Very well.
Q. (BY MR. VICKERY) Did you personally have contact with SmithKline Beecham people at the point of time of these events you're about to relate to us?
A. Yes, I did. The whole way through the 1980s, the early 1990s, I was in very, very close contact with a range of different people from the company.
Q. And is your source of information what you were told by SmithKline Beecham people?
A. Yes, it is.
Q. Okay. Then tell us, if you would, please why it is that they coined the SSRI term.
A. Well, having come to the market after drugs like Prozac, which had a very large market share to begin with, you have got to work out some marketing angle that will help your drug to sell. One of the obvious marketing angles at this point in time was the idea that our drug is cleaner and more selective than drugs like Prozac, and the early adverts here in the US and in the UK also heavily stressed just this point, which was paroxetine was more selective than Prozac and other drugs which are now called SSRIs. Because of this, SmithKline Beecham began saying, "We are the selective serotonin reuptake inhibitor. The others are serotonin reuptake inhibitors. We are the selective one. We are the SSRI." But the acronym was just so good that all of the other companies said, "Oh, that's a good name. We will have it too. We're all SSRIs. And the interesting irony in this is part of the argument put forth by SmithKline Beecham's experts in this particular case is, "What do you know. We're not selective after all. We're a drug that has actions on other brain systems," like the noradrenergic system. Drugs like Prozac, the hint is causes problems, we don't cause the problems because we're not selective," which is an extraordinary irony.
THE COURT: Mr. Vickery, let's take our morning recess at this time.
Q. (BY MR. VICKERY) I want to finish up briefly with your background and credentials and then move into your opinions in this case. Are you a practicing psychiatrist and by that I mean do you see patients?
A. Yes, Mr. Vickery, I look after the area of 25,000 people, would be half the size of Cheyenne, for instance, and I look after all of those psychiatric needs in that area. I spend half my week doing clinical work and the other half doing research or university work.
Q. Do you prescribe Paxil or the other SSRI drugs?
A. Yes, I do, Mr. Vickery. I am a supporter of the SSRI group of drugs. I use them regularly in my clinical practice.
Q. Do you have one you use more than others or how does it divide out?
A. For a number of reasons -- let me put it like this to you. I sit on the hospital formulary group where I'm the person who actually advises on what drugs are used actually within psychiatry and I've picked two of the SSRIs. The ones I've picked for the formulary committee are Zoloft and Celexa. We didn't pick Prozac because in a hospital group of people this drug interacts with all sorts of other drugs that you could be on and lasts for a very long period of time in the body, so it didn't seem to be a good drug to give to people who are ill for other reasons and on a range of other drugs. Paroxetine we didn't pick because in the UK there are great concerns about physical dependence on this SSRI. And the other drug we've got is Luvox which is just the one that is really used least widely.
Q. Okay. Now, are you also a teacher? Do you teach or supervise other doctors, either in the clinical end or in a more academic end?
A. Yes, I am, Mr. Vickery. I teach both students, I teach people who have been qualified for some years and who have gone on to do training in psychiatry, and I also lecture on what are the primary professional training courses for people who are actually going on to be psychiatrists. When they want psychopharmacology covered, places from the university of Cambridge to the university of Liverpool, a wide range of universities ask me to come in and lecture. I also lecture to nursing staff, social workers and a range of other mental health workers.
Q. Are you one of those kinds of people who likes to research and write, publish things in books or journal articles?
A. Yes, I do. I have no idea where you're going with the question, but it is really drawn from -- usually the things that I work on aren't awfully abstract, they're really drawn from clinical experience.
Q. Now, we've talked a little bit about the books or several of your books. How many books total have you published?
A. There's approximately 12 books published or in press. There's a further 100 odd articles published or in press and probably 100 further articles which are nonpeer reviewed articles of one sort or the other.
Q. The first hundred you mentionrd, are those journal articles peer reviewed?
A. Yes, or most all of the ones I've listed in my CV are, yes.
Q. And would you just explain for the jury the sgnificance of having an article published in a professional journal that has been peer reviewed?
A. Yes. Well, the significance is that the article has gone to the journal and the journal then sends the article out to two or three other people in the field. You usually don't know who it is the article has gone to. And these other experts are asked for their views on the issue of have you handled the research that you actually describe in the article in the way the research should have been handled. Now, for instance, if an article were sent to me to review, I would fairly regularly point out to the editor of the journal in the review that I write that this article that's actually come to me is one that has flaws, for instance, that the authors really ought to have done this and this and this. It may be too much to ask them to go back and do the whole thing again, but if they're going to describe the results, they're going to have to point out the limitations of what they've done also, you know, for instance. But fairly often in the course of this process, an article would be turned down by the journal, by a peer reviewer such as me.
Q. Now, have you published in peer reviewed journals articles which express the basic opinion that you're going to give in this lawsuit that for some people the SSRI drugs like Paxil pose an increased risk of violence or suicide?
A. Yes, I have. The first of these articles dates back to 1994.
Q. Have you ever had a journal article that you have written where there hasn't been some peer reviewed publication willing to publish it on these issues?
A. No. The -- no. All of the articles that I've written on this issue have all been published in peer reviewed journals other than one. There's one that has been actually published by the British Medical Ethics bulletin and that, I believe, was not peer reviewed.
Q. And you mentioned something about you reviewing articles. Do you sit on the editorial boards of professional journals, scientific journals, where you are the reviewer rather than the author?
A. I regularly review. You don't have to be on the editorial board to actually review articles. I regularly review articles for about 30 or 40 journals in the field of psychiatry.
Q. Could you give us two or three of the most widely known journals?
A. British Journal of Psychiatry, journals such as Psychological Medicine, the Journal of Psychcopharmacology, the European Journal of Neuropsychopharmacology. I could go on and on.
Q. I think we get the point. We've talked a little bit about some of the research you've done with SmithKline Beecham. Have you conducted other research with SSRI drugs?
A. Yes, I have.
Q. Have you ever conducted any research which involved people who were not depressed -- depression has nothing to do with what happens to them -- that are perfectly healthy where they were on a SSRI drug and one or more of them became suicidal?
A. Yes, I have, Mr. Vickery. I've done two trials. One involves a SSRI given to a group of healthy volunteers. These were nursing staff, medical staff and administrative workers in the unit in which I work. We took 20 volunteers, randomized them either to a drug active on the serotonin system, in this case Zoloft was the one we used, or a drug with no actions on the serotonin system, and in this case the drug we used was a drug called Reboxetine.
Q. Let me stop you there because I think the jury has already heard this word in one of the depositions. Is that a crossover design study?
A. What we did was we took both of the pills and made them up so they looked absolutely the same. You couldn't tell which of the two drugs that people were on. And half of the group had one drug and the other half had the other drug for a two week period in a full clinical dose. They then halt the drug and they're drug-free from whichever drug they've been on for a two-week period and then they cross over and they have the other drug, the one they haven't had before. So all the volunteers got Zoloft and all the volunteers got reboxetine. Half got Zoloft first and Reboxetine second and the other half got Reboxetine first and Zoloft second.
Q. Did any of those volunteer people have absolutely horrible experiences on the SSRI drug Zoloft?
A. Yes, two of the women in the study, and I have to stress again, none of the people -- well, actually as it turned out we found out afterwards courtesy of Pfizer, no less, but one of the people that we had actually recruited had been mildly depressed five years beforehand, but none of the others, and in particular neither of the two people who became very, very suicidal on Zoloft, both of them became suicidal on Zoloft, both of them were women, but none of them had any nervous problems of any sort before they went on this drug or ever before.
Q. And were the results of that study written up and published in a peer reviewed journal?
A. Yes, we did two things. One is we wrote almost instantly what had happened to these two volunteers, these two women who had become very, very suicidal. We wrote that instantly up and sent that off for peer review. The rest of the study has been written up. We have a huge amount of data, we've used all sorts of rating scales, we've used measures to look at the personalities of all of the people who had actually been involved, and we've written that up now and that's gone off to a journal called Psychological Medicine which is probably Europe's premier peer reviewed journal. It hasn't actually been accepted but that's where it's gone.
Q. Very good. Let's move to your opinions in this case. I would like for you to -- I know it is going to take some time for you to explain each and the basis but let's get them all out there and then the jury can kind of follow us where we're going. First of all, with respect to general causation, in your opinion, Dr. Healy, does Paxil cause some patients to become homicidal or suicidal?
A. Yes, it does, Mr. Vickery.
MR. PREUSS: Counsel, could you turn it so we can see that as well?
MR. VICKERY: Sure.
Q. (BY MR. VICKERY) Dr. Healy, were there people who you believe either killed other people or killed themselves as a result of ingesting Paxil before February 13th of 1998?
A. Yes, Mr. Vickery. We know for sure that there were several hundred people who are logged with the FDA who committed suicide or murder/suicide. On the SSRIs as a group the figure is well over 3,000 people on Prozac, Zoloft and Paxil.
Q. Now, are all the incidences of people who have committed murder or suicide on these drugs actually found in the FDA database? Does their system, it in other words, pick up all of the instances?
A. No, Mr. Vickery. If you go into the FDA's website, they themselves say that for serious problems at --
MR. PREUSS: Your Honor, I object. This is clearly beyond the Rule 26 designation.
MR. VICKERY: I don't believe it is, Your Honor.
THE COURT: Well, you will have to show me.
MR. VICKERY: Let me defer and do that. We will keep going.
THE COURT: All right.
Q. (BY MR. VICKERY) Second opinion: Do you believe that SmithKline Beecham has conducted appropriate tests and other forms of investigation with respect to the question of whether and to what extent Paxil causes some people to become homicidal or suicidal?
A. No, I think I'm very clear in my own mind that I haven't and I think you will see from Dr. Blumhardt's video deposition earlier on in the morning that there has not been a single prospective clinical trial that's been designed by SmithKline Beecham to look at the issue of whether people become suicidal on this drug or not.
Q. Third: Do you believe that SmithKline Beecham has given the warnings to the medical profession or others as appropriate considering the risk of homicide, suicide?
A. No, I'm very clear in my mind that they haven't. Again, you heard Mr. Preuss interviewing Christine Blumhardt earlier on during the morning and he himself refers to the fact that the suicide on the warning refers to --
MR. PREUSS: Objection, that was not my voice on the video.
THE WITNESS: Then I'm very sorry, Mr. Preuss.
Q. (BY MR. VICKERY) There was another lawyer questioning Dr. Blumhardt.
A. Right. It is very clear that the warnings that are on the label refer to suicide being caused by people being depressed. There are no warnings there about what this drug can cause.
Q. Finally, with respect to specific causation, did Paxil cause Don Schell to murder or shoot -- murder has a different connotation -- to shoot his wife, his daughter, his granddaughter and then himself?
A. Yes, I believe that it did, Mr. Vickery. I believe that if Mr. Schell didn't have the Paxil that he had been given that he would be alive today and so would his family.
Q. Now let's kind of take these one at a time, and I want to actually start with the second one about their failure to test. First question: Why test? I guess you could say the same thing about a warning. What was there at any point in time that would cause them to want to test or need to test?
A. Well, as I would have understood that issue until fairly recently, it would have been very much on the lines, as I think was indicated in the video yesterday, the article produced by Martin Teicher and Jonathan Cole on Prozac in 1990 was an article by two extremely senior figures in the field. Jonathan Cole is probably the most senior figure in the field. And when people like this describe patients becoming suicidal on Prozac, when they describe it in a way that all but proves there and then that the Prozac has caused these patients to become suicidal, when they're not describing the usual kind of suicidality that happens in the case of people who are depressed, when they're describing a suicidality, when people working in the field for years say, "Look, we've seen people depressed become suicidal, but we've never seen anything like this," when they describe patients who were suicidal before and they say, "Doctor, I've been suicidal before but this is ridiculous," then the field is generally put on notice that there may be a problem with Prozac and other groups of drugs -- all of the other drugs in this group of drugs. I think it was clear from the video yesterday that SmithKline, they took seriously in the first instance this report by Martin Teicher and Jonathan Cole, as did the rest of the field. Now, over the course of the following year or two, a range of other senior people came out and endorsed what Cole and Teicher had found, so by the end of 1991, before Paxil ends up on the market here you have a large body of senior clinical people here in the US saying there is a problem with this group of drugs.
Q. Tick them off for us, either by name or institution that they come from. How many other people, prestigious senior people from prestigious institutions in the United States were writing about this problem in that time frame from February of '90 when the Teicher and Cole article came out until, say, November of '91 when your own article was published?
A. Let's keep mainly to the US and let's not make it too long a list. But we have people like Theodore Van Putten who worked in the University of California. Van Putten was recognized as a leading world expert on akathisia, and in the series of people that he reported on, he says Prozac is causing these people to become suicidal and causing them to become suicidal because it causes akathisia. There was Tony Rothschild and Carol Lock, of whom the senior author on this article was Carol Lock, from Harvard again. And they did a challenge-rechallenge study with Prozac. They had a number of people who had become suicidal on Prozac. The problem cleared up when the drug was halted. They felt happy to do a thing that this court would find fairly risky, I guess, which was to give these people Prozac again. They felt happy to do it because in all three instances the people had done things like jump off buildings and ended up in wheelchairs with broken legs, arms and ribs and couldn't move. So they felt safe giving them the Prozac again to see did the same thing happen. And yes, it did, in all three instances. They found something else which was extremely intriguing. They had a theory about what was actually happening, which was that Prozac was flushing 5HT serotonin onto the serotonin 1 receptor. They argued, if we can block this, that maybe the problem would be eased and in two of the three they were able to ease the problem by using Inderal which is a drug that Dr. Suhany was giving Mr. Schell when he had him on Prozac.
Q. Is that like an antidote?
A. It is not a proper antidote as such in that it minimized the problem rather than cleared it up.
Q. I see.
A. Now, among the others who looked at this were people like Mark Riddle who I believe at the moment is with Johns Hopkins, was probably then with Yale, and this was a group who -- well, Mark Riddle and others who have become some of the senior figures for child psychopharmacology here in the US. They looked at a group of children who had obsessive-compulsive disorder and this is a particularly interesting series of reports because the Lilly defense, as the SmithKline Beecham defense here has been it is the depression not the drug, Riddle and his group looked at a group of children with obsessive compulsive disorder who were not depressed and this group of people, again, also became suicidal. That brings me to a further point which is that Martin Teicher and Jonathan Cole reported on six different people who became acutely suicidal on this drug. They didn't report on all of the patients they had. They didn't in particular report on a 15 year old boy being treated for OCD who became suicidal and killed himself.
Q. Not one of their patients?
A. One of their patients but not one they described.
Q. And being treated with?
A. Prozac.
Q. You have mentioned Riddle was from Yale, Teicher and Cole were from Harvard, right?
A. Yes.
Q. Is Rothschild from Harvard?
A. Yes -- well, then he was but as I say, the senior person there was Dr. Carol Lock and she's still there.
Q. How about Van Putten, where was he from?
A. Van Putten was, as I said, I think UCLA I could have the wrong part of the university but it was one of the bits of the University of California.
Q. I think we get the point, but were there any other major figures in that time period in the United States that were writing about the similar problems?
A. Yes. There were people like John Mann writing about the problem and saying, well, he hadn't seen it. It seemed quite conceivable that this could be happening.
Q. Speaking of John Mann. Did you read Dr. Mann's article, the Mann and Kapur article that came out in September of 1991? Have you read it?
A. Yes, I did.
Q. Have you seen in that article and again in the ACNP paper where he actually recommended four specific ways to test for this?
A. Yes, I did, Mr. Vickery. Yes, I have seen them. Yes.
Q. And has SmithKline Beecham ever done any one of the four types of tests or studies that Dr. Mann himself recommended?
A. No, they haven't.
Q. We have talked about why they should test. Let's talk about how you would test. What kind of a scientific study would be appropriate to nail down a cause and effect relationship between a psycho active drug like paroxetine or Paxil and violent or suicidal behavior?
A. Well, let me begin by bringing out a how you would test thing but that goes back to a why you would test issue that you've asked me before. As I said, as of 1990 SmithKline Beecham and all of the rest of us were aware because of the article by Teicher and Cole that there was an issue here. But in actual fact, all of the companies that produce SSRIs had during the 1980s done studies in healthy volunteers to see what these drugs, the SSRIs do. Now, I was completely unaware of what SmithKline Beecham had done during this period of time until recently, as I was unaware of what (Zoloft manufacturer) Pfizer had done and all of the other companies in the field. One of the very good ways to actually test this would be to do a study in healthy volunteers who aren't depressed. There is a problem, clearly, trying to look at a group of people who are depressed who may also be suicidal, trying to work out does the drug cause you to become suicidal. Though I have to note here that it seems that SmithKline Beecham, (Prozac manufacturer) Eli Lilly and Pfizer have no problems saying that depression causes you to have insomnia and our drug causes you to have insomnia.
Q. Yeah, we heard Dr. Blumhardt say that.
A. Depression causes sexual dysfunction and our drug causes sexual dysfunction; depression causes loss of appetite and our drug causes loss of appetite. They can pick out what's been caused by the drug and what's been caused by the illness. When it comes to people being suicidal, it can't be caused by the drug, only the illness. One way to get around the illness is to go to a group of healthy volunteers, which we did. And I've discovered since that all of the companies have done an extensive body of healthy volunteer work in this area and I believe SmithKline Beecham had the grounds long before 1990 to think that their drug may be causing this problem.
Q. Let's pursue that just a minute. Have you as part -- through your role as a witness in this case been given access to their records of their studies on healthy volunteers that otherwise is not in the public domain?
A. Yes, I have.
Q. Where did you see those records?
A. I went to Harlow where I was actually presented with a vast amount of material. I've been told it is something like 250,000 pages of material or something like that.
Q. is Harlow --
A. In England.
Q. Let me ask you specifics. Is Harlow in England?
A. It is, yes.
Q. And how long were you given to look at this material?
A. I think --
MR. PREUSS: Objection, Your Honor, leading and argumentative.
THE COURT: It is a little leading. Go ahead.
MR. VICKERY: Let me rephrase it.
Q. (BY MR. VICKERY): Would you tell us how long you were allowed to review these records?
MR. PREUSS: Objection, same objection, Your Honor.
THE COURT: It is getting a little technical. Overruled. Let the witness testify.
A. Right. Well, as I understand it, I had to put in a report on my views in this particular case on whatever date it was, March 15th. You actually let me know what the date was. And having actually asked you and I assume you asked them could I have access to the records for some months beforehand, I finally got the opportunity a week before my final report had to be in. I was told that I could have three days. My problem is I also work clinically and I cannot just leave the patients that I've got. I could only take two of those three days because Harlow is close to 200 miles away from where I live and work. So it was a major effort to get there for even those two days. But I put in a full two days working on them. In the course of this afternoon I expect you will see -- the court will be able to see some of the issues. For instance, there's a Montgomery study which is not one of the healthy volunteer studies but it is a reasonably small piece of work that SmithKline Beecham had done and you will see out of that particular study a heap of papers this large.
MR. PREUSS: Objection, Your Honor, not in the Rule 26, the Montgomery study.
THE COURT: Sustained.
MR. VICKERY: Let me move on to something else.
THE COURT: The jury is directed to disregard the testimony.
A. Let me rephrase.
Q. (BY MR. VICKERY) Let me ask you a question and we'll get back on track here. Of the material that you reviewed, can you tell us approximately how many different study protocols on healthy people that they had done that you were allowed to review?
A. Well, I reviewed approximately 34 different studies. I reviewed -- well, I tried to review all of the studies that had been done by SmithKline Beecham with healthy volunteers before the drug had actually been licensed here in the US. When I went there I was told that all of the actual material would be there, but there were at least four healthy volunteer trials from that period that weren't there that I've since asked for and have not been supplied to me. Some of them indicate from the items I have seen severe problems with volunteers dropping out after a single dose of Paxil.
Q. Okay. Is there anything about the material that you did review where they studied this drug on healthy people that helps us answer the question of why should they have done further testing?
A. Yes, there is. It became very clear that the problem with the SSRI group of drugs is that they cause some people to become agitated. They put you into a state of mental turmoil. It is very clear from the healthy volunteer work that SmithKline Beecham did with Paxil during the 1980s that a significant proportion of the healthy volunteers who went on this drug in a placebo controlled way or not placebo controlled way became agitated, at least 1 in 4, a significant proportion, 1 in 6 and in some instances well over half of the volunteers that is go on Paxil drop out because they couldn't tolerate the side effects and often after only a single dose. So, what we clearly have in the 1980s is a record here that SmithKline Beecham were fully aware of long before the Teicher and Cole article comes out that this drug can agitate a significant number of people. A significant number of people who wouldn't have been inclined to complain, because SmithKline Beecham did their studies on their own employees, by and large.
Q. I see. Okay. Now, let's move to how do you test, from why test to how do you test. What is the appropriate way, if you're going to conduct a test, to design and conduct that test in an ethical and proper way you could find out whether and to what extent and to whom this drug poses such problems?
A. Well, one of the ways to do it is the healthy volunteer way. The second way which was worked on extensively for over a year by Lilly and the FDA is to do what is called a challenge/rechallenge protocol. What you do, you take people who become suicidal, for instance, on Prozac in the case of Lilly and you re-randomize them then to either get Prozac again for a second time or to get another drug that has no actions on the serotonin system at all. This would be what you refer to up here as a rich population, not wealthy but these are the kind of people who are the vulnerable group of people that you really want to look at. Lilly drew up the protocol for this, spent over a year working on it. They lined up all the investigators. They had the pills waiting in the blister packs, had everything ready to run, designed a new scale for the emergence of suicidal agitation that was vastly superior to the Beck scale you heard mentioned in the video. And everything was ready to run and Dr. Wheadon whom you've also mentioned was involved in trying to actually design this piece of work, but it has never been conducted. This is the kind of study Dr. Mann recommends should be conducted, hasn't been conducted by any of the companies.
Q. Now, let's talk about rechallenge. Is there a lot of published scientific literature about challenge, dechallenge and rechallenge as a means to prove cause and effect from a drug?
A. Yes. Challenge, dechallenge and rechallenge of dose-response curves, are the only way to prove cause and effect. Randomized control trials won't do it for you.
Q. They won't?
A. No, they won't.
Q. What do they prove?
A. Let me give you an example, okay, and this will help the court. Let's say we take alcohol and everyone in this court will know that we know that alcohol makes you drunk because you take the drug and within, you know, half an hour to an hour Mr. Preuss would have said from his opening remarks this couldn't happen so quickly, you know, on just a small bit of alcohol, maybe two gins or whatever, but within a half an hour you know that this drug is having an effect on you. While the drug wears off, you realize the effect wears off also. You then take your next drink, maybe the next day, and you get the same effect. And everyone in this court knows that alcohol does what it does because of that. But --
Q. Let me stop you and follow up on that a minute. Let's say the first day I took my alcohol with gin and I had too much and I became inebriated so I have a pretty strong feeling that the alcohol in the gin caused that, right? What if the next day when I was rechallenging myself I used vodka? Is that any different in terms of proving the cause and effect?
A. Oh, absolutely. That makes it really much clearer that it is nothing to do with juniper or whatever is in gin and nothing to do with wheat or whatever is in vodka, it is to do with the alcohol. This is actually the common element in the whole thing.
Q. We have a challenge and dechallenge and you were about to explain the rechallenge process?...
...Continued August 28, 2002...
5:53 PM
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