1 1 NO. 90-CI-06033 JEFFERSON CIRCUIT COURT DIVISION ONE 2 3 4 JOYCE FENTRESS, et al PLAINTIFFS 5 6 VS TRANSCRIPT_OF_THE_PROCEEDINGS __________ __ ___ ___________ 7 8 9 SHEA COMMUNICATIONS, et al DEFENDANTS 10 11 * * * 12 13 14 WEDNESDAY, NOVEMBER 9, 1994 15 VOLUME XXXII 16 17 * * * 18 19 20 21 _____________________________________________________________ REPORTER: JULIA K. McBRIDE 22 Coulter, Shay, McBride & Rice 1221 Starks Building 23 455 South Fourth Avenue Louisville, Kentucky 40202 24 (502) 582-1627 FAX: (502) 587-6299 25 2 1 2 I_N_D_E_X _ _ _ _ _ 3 WITNESS: RAY FULLER, Ph.D. _______ 4 By Mr. McGoldrick........................................ 8 5 * * * 6 Reporter's Certificate...................................202 7 * * * 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 3 1 2 A_P_P_E_A_R_A_N_C_E_S _ _ _ _ _ _ _ _ _ _ _ 3 FOR THE PLAINTIFFS: 4 PAUL L. SMITH 5 Suite 745 Campbell Center II 6 8150 North Central Expressway Dallas, Texas 75206 7 NANCY ZETTLER 8 1405 West Norwell Lane Schaumburg, Illinois 60193 9 10 FOR THE DEFENDANT: 11 EDWARD H. STOPHER Boehl, Stopher & Graves 12 2300 Providian Center Louisville, Kentucky 40202 13 JOE C. FREEMAN, JR. 14 LAWRENCE J. MYERS Freeman & Hawkins 15 4000 One Peachtree Center 303 Peachtree Street, N.E. 16 Atlanta, Georgia 30308 17 JOHN L. McGOLDRICK JOHN F. BRENNER 18 McCarter & English Four Gateway Center 19 100 Mulberry Street Newark, New Jersey 07102 20 21 * * * 22 23 24 25 4 1 The Transcript of the Proceedings, taken before 2 The Honorable John Potter in the Multipurpose Courtroom, Old 3 Jail Office Building, Louisville, Kentucky, commencing on 4 Wednesday, November 9, 1994, at approximately 9:05 A.M., said 5 proceedings occurred as follows: 6 7 * * * 8 9 JUDGE POTTER: There are a couple of things that 10 need to be looked at. One is the Defendant's motion about 11 your progress. My thought was I don't know who's leaving town 12 or what, but maybe Friday afternoon set aside some time, like 13 at 1:00, get it decided rather than just pass it along. Mr. 14 Freeman or Mr. Stopher? 15 MR. FREEMAN: That's fine. 16 JUDGE POTTER: All right. And except for just 17 the day-to-day things, that's the only thing that's really 18 hanging in the eaves; right? 19 MR. SMITH: I believe so. And you're speaking 20 of our -- 21 JUDGE POTTER: Well, you've tendered 22 interrogatories and they've said they don't want to answer it 23 for various reasons, and we need to get that sorted out. Did 24 you talk to Mr. Foley about the depositions in Georgia? 25 MR. SMITH: No. I didn't see him yesterday 5 1 afternoon and I saw him briefly this morning. He was in the 2 men's room doubled over. He has kidney stones and he was 3 going to the doctor. 4 MR. STOPHER: Who does? 5 MR. SMITH: Mr. Foley. 6 JUDGE POTTER: I know they're not that serious, 7 but apparently they are very, very painful. But, I mean, it's 8 not going to take place -- it's not scheduled for 10:00 today. 9 Wasn't it the 11th? 10 MR. SMITH: The last I heard, he was not able to 11 get in touch with the lawyers to find out what the 12 availability of the witness was. 13 JUDGE POTTER: But it's not taking place this 14 morning? 15 MR. SMITH: No. 16 JUDGE POTTER: Okay. Mr. Freeman, do you feel 17 okay to introduce Mr. McGoldrick or do you want me to do it? 18 MR. FREEMAN: I'll do it, Judge. 19 JUDGE POTTER: Okay. 20 SHERIFF CECIL: All rise. The Honorable Judge 21 John Potter is now presiding. All jurors are present. Court 22 is now in session. 23 JUDGE POTTER: Please be seated. 24 Ladies and gentlemen, did any of you have any 25 difficulty observing my admonition about not obtaining 6 1 information from outside the witness box? All right. 2 How about you, Ms. Franklin? You weren't home 3 reading up before you came in this morning, were you? 4 JUROR FRANKLIN: No, I wasn't. 5 JUDGE POTTER: Okay. Yesterday there was an 6 exhibit introduced and there was not a copy, and I'm going to 7 -- this is Exhibit No. 390 that was already introduced but you 8 weren't given copies. My sheriff will now pass out copies to 9 you. 10 SHERIFF CECIL: (Hands document to jurors). 11 JUDGE POTTER: While she's doing that, I think 12 it -- I don't know if you liked or disliked the voting last 13 night, but it was exciting, wasn't it? Cliff-hanger locally 14 and then ups and downs nationally. It's tempting to give you 15 my views, but I don't know your views so... 16 Okay. Mr. Freeman, do you want to call your 17 next witness? 18 MR. FREEMAN: Your Honor, I'd like to introduce 19 at this time John McGoldrick, John Brenner from the firm of 20 McCarter & English. They will be examining some of our 21 witnesses. Mr. McGoldrick is from New Jersey. 22 MR. McGOLDRICK: Good morning, Your Honor. 23 JUDGE POTTER: I take it no one on the jury 24 knows either one of these gentlemen? 25 Mr. McGoldrick, do you want to call your next 7 1 witness? 2 MR. McGOLDRICK: Yes, Your Honor. I'd like to 3 call Doctor Ray Fuller, please. Doctor Fuller. 4 JUDGE POTTER: Ladies and gentlemen of the jury, 5 just to save you a little background, I'm sure you feel like 6 you've heard his name. His deposition was read to you earlier 7 by the Plaintiffs; he couldn't be here, but he's now here to 8 testify. 9 Doctor Fuller, will you raise your right hand, 10 please. 11 12 RAY FULLER, after first being duly sworn, was 13 examined and testified as follows: 14 15 JUDGE POTTER: Okay. Would you walk around, 16 have a seat in the jury box (sic), state your name loudly and 17 then spell it, please. 18 DOCTOR FULLER: My name is Ray Fuller. 19 F-U-L-L-E-R. 20 JUDGE POTTER: And answer Mr. McGoldrick's 21 questions. 22 23 24 25 8 1 EXAMINATION ___________ 2 3 BY_MR._McGOLDRICK: __ ___ ___________ 4 Q. Good morning, Doctor Fuller. 5 A. Good morning, sir. 6 Q. Just preliminarily, that little brown thing in 7 front of you is the microphone, so be aware of that. You may 8 not want to move it around too much because it might make some 9 noise or something. And try and keep your voice up, but I 10 think the jury will be able to hear you. 11 Doctor, first of all, could you give the jury 12 your address? 13 A. Yes, sir. I live at 1008 Hudson Bay Drive in 14 Greenwood, Indiana. 15 Q. Are you married, sir? 16 A. I am married. 17 Q. Any children? 18 A. I have two children, a son and a daughter. 19 Q. And how old are they? 20 A. Let's see. My son is 34 and my daughter is 30. 21 Q. Any grandchildren? 22 A. I have three grandchildren. 23 Q. Any of those children live with you? 24 A. No. 25 Q. Just you and your wife at home? 9 1 A. That's correct. 2 Q. Any pets? 3 A. I have one dog. 4 Q. Doctor, have you ever been a witness in a trial 5 before today? 6 A. No, sir; I have not. 7 Q. What is your job today? What do you do? 8 A. I work in research at the Lilly Research 9 Laboratories, Eli Lilly and Company in Indianapolis. 10 Q. And you have -- your title is there? 11 A. My title is Lilly Research Fellow. 12 Q. And could you tell the jury a little bit about 13 what that means? What is a Lilly research fellow? 14 A. Well, it is a position on what we call the 15 research ladder. My job involves doing research related to 16 the brain and the discovery of drugs that may be useful in 17 psychiatric or neurologic or other diseases, and I'm one of 18 the more senior scientists in the research laboratories. 19 Q. Are there any neuroscientific research jobs that 20 are any higher than Lilly research fellow? 21 A. There is actually one title higher than that. 22 Q. And how many Lilly research fellows are there? 23 A. I think there are about six of us. 24 Q. And about how many scientists of any sort work 25 in the scientific aspect of -- I'm not talking about all 10 1 employees, just the scientists? 2 A. I'm not sure I know the exact number, but it's, 3 I guess, between -- 3,000 or so. 4 Q. Okay. And do you do basic research or applied 5 research? 6 A. Well, I really do both. I do research that is 7 intended to help us understand better the brain and how it 8 functions and sometimes dysfunctions, but certainly a major 9 objective in all of my research is to discover and develop 10 drugs that will be useful in treating diseases, so I would 11 consider that applied research. But much of what I do is 12 basic research. 13 Q. Could you just tell us a little bit more about 14 the distinction between basic research and applied research? 15 Maybe you've just said that. 16 A. Well, I think what I understand by those terms 17 is that basic research has the major purpose of simply 18 advancing our knowledge about some area of science, in this 19 case, the body and specifically the brain and the nervous 20 system; whereas, applied research would have an objective of 21 finding, in this case, a medicine or in other cases finding a 22 surgical procedure or something else of that sort. 23 Q. All right, Doctor. I'd like to turn to some of 24 your beginnings in education. Where do you come from, sir? 25 A. I was born near a little town called Dongola, 11 1 Illinois, about 200 miles southwest of here, probably. 2 Q. Southwest where, where is that? 3 A. In the very southern tip of the state of 4 Illinois. 5 Q. I see. Were you born in a city, town, where? 6 A. I was born on a farm. 7 Q. And how long did you live there? 8 A. I lived there during my early childhood. We 9 moved into a little town when I was in the seventh grade. 10 Q. In your early childhood did you expect to go to 11 high school? 12 A. No, actually I didn't. This was a fairly remote 13 area at that time and there were no such things as school 14 buses, and the nearest town was about seven miles away, so I 15 didn't have any way of getting there. I didn't expect to go 16 to high school, no. 17 Q. What happened in that respect? 18 A. My parents actually moved into this little town 19 when my brother was in the eighth grade and I was in the 20 seventh, primarily so that we would have a chance to go to 21 high school. 22 Q. And you went to high school where? 23 A. I graduated from the Anna Jonesboro Community 24 High School. 25 Q. What did you do after you went to high school, 12 1 sir? 2 A. I enrolled at Southern Illinois University in 3 Carbondale. 4 Q. And did you take a degree from that university? 5 A. Yes. I received two degrees there. I received 6 a Bachelor's Degree in chemistry and a Master's Degree in 7 microbiology. 8 Q. So we're clear, the first degree is in chemistry 9 and that's the college or undergraduate degree? 10 A. That's correct, yes. 11 Q. And how many years was that? 12 A. Four years. 13 Q. And then you took a graduate degree in -- what 14 did you say, microbiology? 15 A. In microbiology. I spent two years working for 16 that degree. 17 Q. And after that degree, what did you do next? 18 A. I moved to Indiana to attend Purdue University 19 and work toward a doctorate in biochemistry. 20 Q. When you were doing your studies, your Master's 21 Degree at Southern Illinois in microbiology, what sorts of 22 things did you study? You don't have to give us the whole 23 course, but what did you study? 24 A. Well, of course, microbiology is the study of 25 microorganisms, bacteria, yeast and viruses and things of that 13 1 sort. I specifically was working on yeast, measuring 2 biochemical processes. I was interested in biochemistry, so I 3 worked on biochemical processes in these small, living cells. 4 Q. And then when you went to Purdue you took a 5 three-year course leading to your doctorate or Ph.D. Did you 6 have any specialty there or just sort of general biochemistry? 7 A. Well, I took general biochemistry courses, but 8 the research that I did for my dissertation involved the blood 9 coagulation system, particularly proteins involved in breaking 10 down blood clots. 11 Q. Now, Doctor, during the time that you were in 12 college and getting your Master's Degree at Southern Illinois, 13 did you work in addition? 14 A. Yes. I worked in different jobs during that 15 period of time. 16 Q. Did you have occasion to work in a mental 17 hospital during that period? 18 A. Yeah. Beginning early in my college years, I 19 worked in a state hospital in my hometown of Anna, Illinois; 20 it was called the Anna State Hospital. It was a large state 21 mental hospital. I worked there off and on summers and 22 weekends during all of the six years that I spent at Southern 23 Illinois. 24 Q. And this was in part to work your way through 25 school? 14 1 A. It indeed was for that purpose, yes. 2 Q. And can you tell us what you did there and what 3 life in a mental hospital in that era was like? 4 A. Well, I did various jobs during the period of 5 time I worked there, but most of the time I was working 6 actually as a ward attendant in the state hospital, helping to 7 take care of the patients who were in there. 8 Q. And about -- over what period of years would you 9 say you worked there? You were a young man, in college -- a 10 younger man, I should say. 11 A. A younger man. That actually was in the early 12 1950s. I think I started there in 1953 to 1958, probably. 13 Q. Was that tough duty, a hard job? 14 A. There were aspects of it that were pretty tough 15 and certainly unpleasant. 16 Q. Could you just explain that to the jury just a 17 little? 18 A. Well, for example, when I began working there as 19 a ward attendant I worked on the late-night shift from 11 P.M. 20 to 7 A.M., I think. And I always remember the first night I 21 started working there because about an hour into the shift one 22 of the patients became violent, and the other ward attendant 23 was a 60-year-old lady who was smaller than I was and I wasn't 24 very big at that time. And we were supposed to go in and take 25 control of that situation, and we didn't exactly know how to 15 1 do that, so we ended up having to call for reenforcements. 2 But it was a very eventful evening, and it gave me an early 3 impression of what life on a mental ward of a state hospital 4 in those days was really like. And I saw a lot of things 5 during the years that I worked there that were tragic. 6 Q. Did that change at all while you were there or 7 later? 8 A. It really changed dramatically while I was 9 there. It was during the period of time that I worked there 10 that the class of drugs called the phenothiazines was 11 introduced for the people who had schizophrenia, and those 12 drugs made a big difference to the lives of schizophrenic 13 patients and their families and certainly on those mental 14 hospital wards at that time. 15 Q. Was that among the early medicines used to treat 16 mental disease? 17 A. Yes. The phenothiazines are usually pointed to 18 sort of the beginning of modern psychopharmacology. 19 Q. And about what year would that have been, 20 roughly? 21 A. It was the mid 1950s. 22 Q. Did your work at the Anna State Hospital have 23 anything to do with your choice of a career as a scientist and 24 a neuroscientist? 25 A. Yes, it certainly did. When I was finishing my 16 1 studies in biochemistry, I had been very impressed with the 2 fact that in those days we didn't know much about mental 3 illness and how to deal with it, and I decided that if I ever 4 finished my education I wanted to work trying to understand 5 better the biochemistry of the brain, how the brain works and 6 why it doesn't work right sometimes and what might be done 7 about that. And that's what drove me to work in the area that 8 I've worked in. 9 Q. And is that what you've done during your life? 10 A. Yes, it is. 11 Q. Let's go back then. We've got you to the point 12 where you've finished your education and the undergraduate 13 degree in chemistry, the master's and the doctorate at Purdue. 14 What did you do next? 15 A. The first job I took was at another state 16 hospital, this time in Fort Wayne, Indiana, and it was a state 17 hospital for mentally retarded as opposed to mentally ill, so 18 that most of the patients came into this hospital while they 19 were children and most of them then spent the rest of their 20 lives there. 21 Q. And what was your work there, Doctor? 22 A. I went there to begin a biochemistry research 23 program, trying to again study the brain and learn more about 24 how the brain works in biochemical terms and again understand 25 what -- or some of the biochemical bases for brain 17 1 dysfunction. 2 Q. Did you have a title when you were there? 3 A. Well, I was called director of the biochemistry 4 research laboratory, but the lab consisted of myself and two 5 other people. 6 Q. And did you publish any scientific papers or do 7 any work that led to publishing while you were there? 8 A. Yes. We were able to get NIH grants to do 9 research, and we did research and we published papers on that 10 research while I was there, yes. 11 Q. And that was on what subject? 12 A. Well, on written subjects we published -- we 13 particularly studied the condition called Down's syndrome or 14 mongolism, trying to learn more about biochemical 15 abnormalities associated with that disorder, and most of the 16 publications were on that subject. 17 Q. Did you ever receive any inquiries about your 18 work there, even then? 19 A. Yes. We published -- one of the papers we 20 published was in the journal called Science, which is a widely 21 circulated scientific journal. And, of course, when you 22 publish work of that sort and other scientists are interested 23 in it, they will send requests for reprints of that paper so 24 that they will have it for their files, and I received a 25 number of reprints requests for some of those papers, the most 18 1 notable one being from the White House. 2 Q. For -- this for a young man must have been 3 something. Do you remember it? 4 A. I remember it pretty well because the envelope 5 said the White House on the outside and I didn't know what 6 that meant, and when I opened it up I realized it was "the" 7 White House, and it actually was from the personal physician 8 to President John Kennedy, whose name was Janet Travell. 9 Q. And why was she interested in your work? 10 A. I'm not sure, but I've always thought it was 11 because President Kennedy had a mentally retarded sister, and 12 the Kennedy family had a great interest in mental retardation 13 and mental dysfunction. 14 Q. So you were working on biochemical aspects of a 15 particular mental condition, retardation, at Fort Wayne? 16 A. Yes. 17 Q. By that time in the advancement of science in 18 this area, was it recognized generally in science that some 19 mental illnesses are caused by biochemical imbalances? 20 A. Yes. I think it was. I mean, certainly, our 21 entire body is made up of chemical substances and the process 22 of life is one of chemical changes, molecular changes, and I 23 think most scientists understood that the brain is not 24 different from other organs in that regard, that there are 25 chemical processes going on and that when there is some 19 1 abnormality in the function of the brain or some other organ, 2 there are chemical abnormalities that are associated with 3 that. 4 Q. This doesn't mean we don't have a mind or a 5 soul? 6 A. No. We certainly -- we certainly can think. 7 When we think, there are chemical changes going on in our 8 brains. 9 Q. After you did your work at Fort Wayne State 10 Hospital, what did you do next? 11 A. I became frustrated at that institution because 12 it didn't seem like a place one could work productively in 13 research, as productively as I wanted to, and so I looked 14 around for another place to work in a better research 15 environment and I ended up moving to the Lilly Research 16 Laboratories. 17 Q. What attracted you to that place? 18 A. Well, they were looking for a biochemist to come 19 in and help in the search for drugs for treating mental 20 illnesses, and that was exactly an area that I wanted to work 21 in and it seemed like a good opportunity. 22 Q. What was the reputation of the science and the 23 scientists at the Lilly labs at that time? 24 A. Well, I think it was very good. When I first 25 learned about the job, I didn't honestly know a lot about the 20 1 company. But one of the things that led me to end up going 2 there was a close friend of mine who had become a pharmacist 3 and owned a drugstore over in Illinois; when he learned I was 4 considering moving to Lilly, he strongly encouraged me to do 5 so by telling me that that company had a particularly good 6 reputation among drug companies and that it would be a good 7 place for me to work, so I listened to his advice. 8 Q. After about 30 years how have you found it to 9 be? 10 A. I have found it indeed to be a very good place 11 to work. 12 Q. What were your research interests initially when 13 you first came to Lilly? 14 A. Well, they were generally what they had been, to 15 study the brain in biochemical terms. Specifically, I went 16 there to do some work on a group of compounds that were called 17 monoamine oxidase inhibitors. These are drugs that had 18 potential use in treating mental depression, and we needed to 19 characterize these particular compounds better to see if they 20 did have the right properties that would allow them to be 21 developed as drugs. 22 Q. And how was it that you -- strike that. 23 Did you come to work at some point with Prozac 24 or fluoxetine, as we know it? 25 A. Yes. I began working on the particular 21 1 neurotransmitter called serotonin when I first joined the 2 Lilly Research Laboratories in 1963, and I was then involved 3 in the early work on Prozac or fluoxetine when it was first 4 made and studied about nine years later. 5 Q. About how many years now have you been working 6 with serotonin, brain research and Prozac? 7 A. Well, I've been working in brain research, I 8 guess, for 33 years; I've been working on serotonin for at 9 least 31 years; and I've been working on Prozac for 22 years. 10 Q. While you've been at Lilly have you worked on 11 any other medicines which are used to help people with 12 disease? 13 A. One medicine that I worked a lot on is a 14 medicine called Permax, which is pergolide. It's used in the 15 treatment of Parkinson's disease, which is a neurologic 16 disease. 17 Q. And you worked on bringing that medicine to 18 development? 19 A. Yes. We did again the biochemical studies that 20 showed that compound was a potent dopamine agonist in animals 21 and that it was effective in animal models of Parkinson's 22 disease. 23 Q. How many people roughly -- I'm sure this has to 24 be an approximation, but over the years about how many people 25 at Lilly, how many scientists and other people, mostly 22 1 scientists let's focus on here, have been working on serotonin 2 research and Prozac? 3 A. Well, there's been an increasing number working 4 on serotonin. Serotonin continues to be a transmitter that we 5 are very interested in in our research laboratories, and an 6 increasing number of scientists have worked or are working on 7 serotonin as a transmitter. Certainly scientists working on 8 Prozac because there are so many aspects in the development of 9 a new medicine, there's been hundreds, perhaps a thousand or 10 more, who have worked on some aspect of Prozac during its 11 development. 12 Q. All right. Let me turn to another subject for a 13 minute, Doctor Fuller. I think the jury has heard about it in 14 this trial, but can you explain what the medical literature 15 is? What does that mean? 16 A. Well, when research is done in the field of 17 medicine and science, the findings are written up in the form 18 of papers or publications which appear then in journals, 19 medical journals and other scientific journals. These are 20 typically -- would look like the magazine you might buy on the 21 newsstand, except the content is entirely technical and 22 therefore of interest only to other scientists and libraries, 23 medical libraries and that sort of thing. And these are 24 typically what we call peer-reviewed journals. The contents 25 are evaluated by other scientists and judged worthy of 23 1 publication before they actually appear; some papers are 2 judged unworthy of publication and never make it into the 3 medical literature. 4 Q. And have you published your work that you've 5 done at Lilly in the scientific and medical literature? 6 A. Yes. I've published a great deal of our work. 7 Q. When you published that, the work you were doing 8 was available to the entire scientific world? 9 A. That's correct. 10 Q. Available for criticism or comment or whatever? 11 A. That's correct. Hopefully available for use. 12 Q. Have others besides people at Lilly like you 13 been publishing in this field in the medical literature over 14 this period of time? 15 A. Yes, we do. We have a lot of publications 16 coming out of Lilly Research Laboratories every year. 17 Q. And others outside of Lilly, scientists over the 18 world publish in this literature? 19 A. Yes, of course. 20 Q. How many scientific or medical papers have you 21 published, approximately? 22 A. I think somewhere around 500. 23 MR. McGOLDRICK: Is that me, Your Honor? 24 JUDGE POTTER: I don't know. That's a new 25 sound, isn't it? 24 1 Q. All right. Why don't we try to continue, 2 Doctor. You're not a physician, you're not a medical doctor? 3 A. That's correct. I have a Ph.D. Degree in 4 biochemistry. 5 Q. But you've published in scientific journals and 6 indeed in some medical journals? 7 A. Yes. That's correct. 8 JUDGE POTTER: I tell you what, ladies and 9 gentlemen, why don't we take a ten-minute recess till we 10 figure out what this new sound is. We can live with some of 11 them, but that one is a little heavy. 12 As I mentioned to you-all before, do not permit 13 anybody to talk to you about this case, communicate with you 14 about any topic connected with this case; do not discuss it 15 among yourselves or form or express opinions about it. We'll 16 take a ten-minute recess. 17 (RECESS) 18 SHERIFF CECIL: The jury is now entering. All 19 jurors are present. Court is back in session. 20 JUDGE POTTER: Please be seated. Doctor Fuller, 21 I'll remind you you're still under oath. 22 Mr. McGoldrick. 23 MR. McGOLDRICK: Thank you, Your Honor. I hope 24 we got this fixed. 25 Doctor, before the break we were talking about 25 1 the medical literature and scientific articles and those 2 you've published, and I think you said, or perhaps you did, 3 approximately how many papers you've published. 4 A. I think approximately 500, maybe a little bit 5 less. 6 Q. And what's the general subject matter of the 7 scientific work you've done that's come out in those papers? 8 A. Well, they almost all have dealt with 9 neurochemical studies on the brain and the effects of 10 different drugs on processes in the brain. Mostly I have 11 worked with I guess about four particular neurotransmitter 12 substances: serotonin, dopamine, norepinephrine and 13 epinephrine. 14 Q. Are there a variety of scientific journals in 15 which you've published? 16 A. Yes. I've published in a number of different 17 journals, mostly neurochemical journals and pharmacological 18 journals, because my studies have often involved the study of 19 the effect of medications on particular processes in the 20 brain. 21 Q. And are you generally familiar with the people 22 who publish a lot and are the known leading scientific figures 23 in that area? 24 A. Yes. I certainly know the neurochemical, 25 neuroscience and pharmacology literature I think very well. 26 1 Q. Do you try to stay on top of that literature and 2 read it and be aware of it? 3 A. I spend a lot of time trying to do that. 4 Q. Is that part of your job? 5 A. Yes, sir. 6 Q. Are you aware of a man named Peter Breggin 7 having published in that field? Is he a big name in that 8 field? 9 A. No. He is not a big name. 10 Q. Little name in that field? 11 A. I don't think many neuroscientists or 12 neuropharmacologists would know him. 13 Q. Have you collected your articles, sir, in a 14 resume or a curriculum vitae or whatever we call it? 15 A. Yes. They're all listed in my CV or curriculum 16 vitae. 17 Q. All right. Let me see if I can come and get 18 that for a minute. I believe this is Exhibit 205, which I'll 19 give to Doctor Fuller, to Your Honor, Mr. Smith. 20 Doctor Fuller, what's this? 21 A. This is my CV. 22 Q. In general, what does it contain? 23 A. Well, it contains information about where I was 24 born, educated, and positions I've held and other scientific 25 activities that I have done or am doing. 27 1 Q. Does it include a listing of scientific 2 societies you're a member of? 3 A. Yes, it does. 4 Q. What is a scientific society and what does it 5 do? 6 A. Well, it's an organization made up of scientists 7 interested in a particular area, like biochemistry society or 8 neuroscience society or a pharmacology society. 9 Q. And these are collections of experts in that 10 field? 11 A. Yes. That's correct. 12 Q. Those scientific societies, are you a member of 13 any? 14 A. I'm a member of several. 15 Q. Are those listed in your CV? 16 A. Yes, they are. 17 Q. Do these scientific societies, are they the 18 ones -- many times are they the ones who publish these 19 scientific articles, the medical literature you were talking 20 about? 21 A. Yes. Most of these societies have one or more 22 journals which they publish and they are responsible for, and 23 they typically take pride in the scientific quality of those 24 journals. 25 Q. And those journals have editorial boards, do 28 1 they? 2 A. Yes, they do. 3 Q. And what's the function of the editorial board 4 of one of these scientific journals? 5 A. The editorial board is responsible for the 6 scientific accuracy and quality of the publications in that 7 journal, so the editorial board has the job of evaluating 8 manuscripts that are submitted for publication, either by 9 making judgments themselves or, in some cases, by finding 10 expert referees or reviewers to assess the quality of those 11 manuscripts. 12 Q. Are you a member of any editorial boards? 13 A. Yes. I'm a member of several editorial boards. 14 Q. Are you a member of any of the editorial boards 15 of any of the leading journals in this field of brain research 16 and brain medicine? 17 A. Well, I'd like to think these are some of the 18 leading journals, yes. 19 Q. What are the names of some of those? 20 A. Well, I'm on the editorial board of the Journal 21 of Pharmacology and Experimental Therapeutics, on the 22 editorial board of Neurochemistry International, Biochemical 23 Pharmacology and Drug Development Research. 24 Q. Now, you've talked before and I think others 25 have talked in this trial about a peer review. This is review 29 1 of articles by experts before they get published? 2 A. Yes. 3 Q. Who does that peer review? 4 A. That is done by members of the editorial board 5 or by other scientists that they call upon to make that 6 assessment. 7 Q. Have you -- are you called upon to be those 8 experts who review the work of other scientists yourself? 9 A. Yes. I do that regularly. 10 Q. And about how many papers a year would you 11 review for this purpose to see if they're worthy of 12 publication, if you can give us a rough? 13 A. It probably varies but it's probably on the 14 average of 60 -- at least one a week, let's say, 50 or -- 50 15 to 70 or more per year. 16 Q. And the papers that you published or the great 17 proportion of them, have they been in peer-review journals? 18 A. Yes, they have. 19 Q. So other scientists have reviewed them to see if 20 they make it to publication? 21 A. Yes, they have. 22 Q. Does everything that gets submitted in peer 23 review get published? 24 A. No. Not by a long shot. Some of the journals 25 that I'm on the editorial board for, I think we only accept 30 1 maybe 20 percent of the manuscripts that are submitted for 2 publication. Some journals it's a little more than that, 3 maybe some even less. 4 Q. And your papers, the ones that you've actually 5 written are listed in this CV, this document that you're 6 holding? 7 A. Yes, they are. 8 Q. Are they all listed there? 9 A. I think it's up to date. 10 Q. Your Honor, I'd like to offer that and have it 11 published to the jury. 12 JUDGE POTTER: Be admitted. What is the number 13 on it? 14 MR. BRENNER: 205, Your Honor. 15 SHERIFF CECIL: (Hands document to jurors). 16 Q. Now, Doctor, I promise you and I promise the 17 jury I would not go through this whole thing, but just so we 18 know what it is, the first couple of pages are personal data 19 and your education and background we've been through. Then on 20 Page 2, we have your positions and your membership. Then at 21 the bottom of Page 2, where it says Scientific Services, what 22 do you have under that? 23 A. Well, that's a listing of the journals on which 24 I serve on the editorial board. 25 Q. And turning over to the next page, Manuscript 31 1 and Book Reviewer, I guess that's obvious, for all those 2 journals that are listed? 3 A. Yes, sir. 4 Q. Going over to the next page, it says Grant 5 Proposal Reviewer For, and then lists a whole bunch of things, 6 like the Air Force Office of Scientific Research and British 7 Columbia Health Care, a whole bunch of stuff. What does it 8 mean to be a grant proposal reviewer? 9 A. Well, most scientific research basically at 10 medical schools and academic institutions is funded by grants 11 from various agencies, particularly these government agencies 12 like the National Institutes of Health and then there are 13 various private agencies. And then the proposals that are 14 submitted with a request for funding need to be evaluated by 15 experts in the field of that research, and so I volunteer time 16 reviewing those grant applications. 17 Q. And I can't resist asking you about one. Down 18 in the middle of that page there's something called the 19 President of the Catecholamine Club. I've heard of chess club 20 and football teams and rugby clubs and stuff like that. 21 What's a catecholamine? 22 A. Well, catecholamines are a particular class of 23 chemicals. They include norepinephrine, epinephrine, and 24 dopamine. They are substances present in the adrenal gland, 25 for example, but present also in the brain, and so scientists 32 1 who are interested in those particular substances, 2 catecholamines, have banded together to form a club called the 3 catecholamine club. 4 Q. Just folks who have an interest in that molecule 5 called catecholamine? 6 A. That's correct. 7 Q. All right. And you've got a lot of these other 8 things -- I won't go through them. Next page, 6, Lectures and 9 Seminars, and then you've got a bunch of pages after that. I 10 gather you give lectures and seminars. What typically -- who 11 asks you to give a lecture and what do you talk about? 12 A. Well, I talk about the research that we have 13 done in some particular area. These are typically in medical 14 schools and universities, departments such as the pharmacology 15 departments or psychiatry departments or that sort of thing. 16 Q. And these are the titles of different lectures 17 and seminars you give? 18 A. Yes, sir. 19 Q. All right. Let's keep going, more pages, more 20 pages. Page 13, a whole bunch of meetings -- scientific 21 meetings you've had something to do with, they're all listed? 22 A. Yes, they are. 23 Q. And then we go to Page 16, Publications? 24 A. Yes, sir. 25 Q. And that goes all the way to Page 61. Have -- a 33 1 lot of these papers relate to serotonin? 2 A. Many of them relate to serotonin, yes. Some of 3 them relate to the catecholamines and some relate to other 4 topics that I've done research on. 5 Q. And is there work in here publishing about 6 fluoxetine, Prozac, and other possible medicines? 7 A. Yes. The work on Prozac would start in exactly 8 1974, and there are a number of publications then since then. 9 Q. Now, I think I just made a mistake. I said the 10 publications went from Page 16 to Page 61 or so. Actually 11 they go to Page 44, and on Page 45 you have list of abstracts 12 and presentations? 13 A. Yes, sir. 14 Q. What's an abstract? 15 A. Well, these are presentations at scientific 16 meetings, and typically one publishes a short abstract and 17 then the actual presentation at the meeting would either be a 18 talk, maybe a ten-minute oral talk, occasionally a longer one, 19 or in the form of a poster. 20 Q. All right. And, Doctor, the last page is book 21 reviews. These are just reviews that you've written of other 22 people's books in this field? 23 A. That is correct. 24 Q. And you've written your review for some journal? 25 A. Yes. That's right. 34 1 Q. All right. Let's put that aside. Now, unless 2 we take the whole day or week on this, let me try and cut some 3 of this short. You have studied medicines affecting neurology 4 and brain function in a variety of species, have you? 5 A. Yes, I have. 6 Q. About how many? 7 A. Well, most of our studies have been in 8 laboratory rats and mice but some have been in other species, 9 guinea pigs. We've done some work in cats, dogs, and other 10 species, as well. 11 Q. All right. And without going through them all, 12 have you studied numerous kinds of compounds or potential 13 medicines or medicines? 14 A. Yes. We've studied enzyme inhibitors, receptor 15 agonists and antagonists and a lot of different kinds of 16 medicines that have different actions on the brain or some 17 other part of the body. 18 Q. Dozens or maybe even 100 or more? 19 A. Probably. That's correct. 20 Q. Okay. And different body systems. Have you 21 studied -- you said you've studied nerves, neurochemistry, 22 brain function, et cetera, have you studied any other body 23 systems with all of these other different things you've 24 studied? 25 A. Yes. I've studied the adrenal gland a lot. 35 1 I've studied the liver, I've studied the heart, and I've 2 studied other organs in the body. 3 Q. And what about neurotransmitters, have you 4 studied many of those? 5 A. Yes. A great deal of our work has related to 6 neurotransmitters, either in the brain or in some other part 7 of the body. And we've studied various different 8 neurotransmitters, but particularly the catecholamines, the 9 three that I mentioned: dopamine, norepinephrine, epinephrine 10 and serotonin. 11 Q. And does your work either experimental or in 12 literature and writings include different kinds of behaviors 13 that you've tried to follow? 14 A. Yes. In general, we have tried to correlate 15 neurochemical changes that we measure with some kind of 16 functional change, whether it's a behavioral change or 17 endocrine change or any other kind of change associated with 18 that particular neurotransmitter. 19 Q. And you've published a substantial amount of 20 work in this field? 21 A. We try to publish all the work that has a 22 definitive conclusion to it, yes. 23 Q. You continue your work today in these fields? 24 A. Yes, I do. 25 Q. What are your major areas of interest today? 36 1 A. Well, most of my current research does involve 2 serotonin. We are looking at drugs that have an action 3 directly on receptors for serotonin and are interested in 4 those drugs as potentially being useful as therapeutic agents 5 in the treatment of various kinds of mental illnesses and 6 other kinds of diseases. 7 Q. In the course of your work in your life, have 8 you received any awards of any type for your work, sir? 9 A. Well, I've received a few; yes, sir. 10 Q. Well, there's something called the Discoverers 11 Award? 12 A. Yes, sir. 13 Q. What's that? 14 A. The Discoverers Award is given by the 15 Pharmaceutical Manufacturers Association once a year to 16 recognize the discovery of a particularly important drug, in 17 their opinion. 18 Q. Did you receive that? 19 A. I received that award in 1993, along with my two 20 colleagues at Lilly, Doctor Brian Molloy and Doctor David 21 Wong. 22 Q. All right. Well, maybe we'll come back to that. 23 Have you received any honorary degrees? 24 A. I received two honorary degrees; one from 25 Southern Illinois University, and one from Purdue University. 37 1 Q. And what were they recognizing? 2 A. Well, I think they were recognizing my research 3 contributions to the field of neuroscience and 4 neuropharmacology. 5 Q. When you receive an honorary degree you usually 6 get that at commencement time at that school; is that what 7 happens? 8 A. Yes, sir. 9 Q. And you're escorted in in academic procession or 10 something? 11 A. Yes, sir. 12 Q. And there's a citation that is created for the 13 person who receives the honorary degree? 14 A. Yes, sir. 15 Q. And that's typical? 16 A. That is the way it's done, I think. 17 Q. And there was a citation in your case for your 18 honorary degrees? 19 A. Yes. In both cases. 20 Q. All right. Let me see if I can get those. All 21 right. We have two here I'm going to show you -- I guess I'll 22 keep the original -- at the same time so we can move a little 23 quickly, I hope. 24 All right. Doctor, I've shown you two 25 documents, one is marked exhibit -- Defendant's Exhibit 244, 38 1 and the other one is Exhibit 243. Why don't you just tell us 2 what -- identify 244 for us. 3 A. Well, 244 contains a couple of pages from the 4 Southern Illinois University College of Science commencement 5 booklet from May of this year and it has the page that 6 describes I guess why they gave me an honorary degree. 7 Q. Well, there are a lot of reasons. I won't force 8 you to read it and I won't read the whole thing, but let me 9 ask you if it says in part, "Doctor Fuller is recognized by 10 his peers as one of the top neuroscientists in the world." 11 Does it say those words, sir? 12 A. That's a quote from Doctor Ronald Browning; yes, 13 sir. 14 Q. And similarly, let me ask you about 243, Exhibit 15 243. What's that? 16 A. This is a similar couple of pages from the 17 Purdue University commencement booklet in 1990. 18 Q. And that similarly has a description of your 19 work and why they gave you the award? 20 A. Yes, sir; it does. 21 Q. All right. Well, I'm not going to ask you to 22 read that, either, but I'd like to offer these, Judge, and ask 23 that they be published for the jury. 24 JUDGE POTTER: Be admitted. 25 SHERIFF CECIL: (Hands documents to jurors). 39 1 Q. All right. Doctor, if we're ready, I think I'd 2 like to turn to another subject and turn away from your own 3 credentials and accomplishments and turn to -- just briefly 4 try to give us a sense of the development of our knowledge 5 over time in connection with the brain, neuroscience and these 6 kinds of subjects. First of all, we don't know everything 7 about how the brain works, do we? 8 A. No, we certainly don't know everything. 9 Q. How would you describe what the state of our 10 knowledge is? 11 A. Well, I think the increase in knowledge about 12 the brain and about neuroscience has been impressive during 13 the past few decades. I think we've probably made more 14 progress, more rapid progress during recent years in 15 understanding the brain than any other part of the body, 16 partly because we have probably lagged behind prior to that in 17 understanding the brain. But there's been just an incredible 18 increase in the amount of research done in the area of 19 neuroscience and, in particular, in the study of the brain 20 during the past 25 or more years. 21 Q. If we went back, say, 50 years, when Mr. Smith 22 and I were little boys; is that right? 23 MR. SMITH: Forty-nine. 24 Q. If we went back about 50 years, just as an 25 approximation, how would you compare our knowledge then to our 40 1 knowledge today as it relates to the brain, as it relates to 2 mental diseases and how to treat them? Were we primitive 3 then, were we pretty advanced then? How can you mark this on 4 the calendar for us? 5 A. Well, I think we would have to call ourselves 6 primitive back in those days. We certainly didn't have very 7 much at all effective in the treatment of mental illness. Our 8 knowledge about the brain and how it worked was also 9 primitive. There's been a lot of particular neurotransmitters 10 that have been discovered since 50 years ago, during the past 11 50 years. There's many neurotransmitters in the brain that we 12 didn't even know about 50 years ago, and certainly all those 13 that had been discovered and those that had previously been 14 known we've learned a great deal about in the past 50 years, 15 and particularly in more recent years, and one important 16 reason for that is simply that the technology has advanced so 17 much. It's possible to do experimentation -- experiments that 18 simply wouldn't have been possible 50 years ago. 19 Q. When did we first actually discover that a thing 20 called serotonin existed? 21 A. Well, serotonin itself was found in nature in 22 1948; it was actually found to be present in the brain in 23 1953. So everything we know about brain serotonin has been 24 learned since 1953, which is a year I can remember from having 25 been a freshman in college. 41 1 Q. Is it true that in general with all kinds of 2 neurotransmitters, the knowledge we've gained has been recent 3 20th-century kind of knowledge and has been explosive in its 4 growth? 5 A. Yes, sir. That is true. 6 Q. And I think you said earlier that when you were 7 in Anna State Hospital -- if I have that right -- as a ward 8 attendant, that was when the phenothiazines were discovered? 9 A. Yes, sir. 10 Q. And they were medicines to treat what condition? 11 A. Schizophrenia. 12 Q. And we've heard something in this trial -- the 13 jury has -- and will be some more today about tricyclic 14 antidepressants. When were they discovered? 15 A. The antidepressant drugs, including the 16 tricyclic antidepressants drugs, were discovered in the late 17 1950s. 18 Q. And what about the so-called MAOI 19 antidepressants? I think they may have heard about those. 20 A. MAOI stands for monoamine oxidase inhibitor and 21 those are also antidepressant drugs, and they were discovered 22 also about that same time in the late 1950s, a few years after 23 the antipsychotic drugs, antischizophrenic drugs had been 24 discovered. 25 Q. You've told us a little bit earlier about these 42 1 scientific societies that people who gather together who are 2 experts in the field and publish journals and stuff. Are some 3 of the scientific societies for some parts of the body pretty 4 old? 5 A. Yes, sir. There have been physiology society 6 and I think even the biochemistry society, those have existed 7 for a long time. Maybe -- I'm not sure about the United 8 States, but certainly in England, for example, some of those 9 societies are well over 100 years old. 10 Q. And there -- is the Society for Neuroscience, 11 one of the big societies in the field we're talking about? 12 A. Yes, sir; it is. 13 Q. When was that actually founded? 14 A. The Society for Neuroscience was started in 15 1969. 16 Q. And were you a charter member of that? 17 A. Actually, I wasn't a charter member. I joined 18 shortly after that. I think there were only about 500 charter 19 members in 1969. 20 Q. And can you give us a sense of how many there 21 are today? 22 A. I know the society has grown rapidly. I 23 remember it was well over 17,000 -- I think that was in 1990. 24 I remember those numbers. It has grown since then. It's 25 probably in the neighborhood of 20,000 members by now. 43 1 Q. And you've talked about the literature and how 2 it's grown and exploded. Tell the jury about this -- there's 3 a 1994 annual meeting of this neuroscience society coming up? 4 A. That's correct. It's coming up next week. 5 Q. And how many abstracts or posters of the work 6 that's going on in the field are scheduled to be presented at 7 that? 8 A. There are more than 10,000 individual abstracts, 9 individual presentations from different scientists working in 10 the area of neuroscience. 11 Q. So there's been this great growth in our 12 understanding of the brain and its functions. Has that been 13 recognized at all by the national government? 14 A. It's been recognized in a lot of ways, but one 15 way in particular, the United States Congress has declared 16 this to be the Decade of the Brain, the 1990s. And that was 17 announced originally by President Bush, and it was in 18 recognition of the tremendous advances that have been made in 19 understanding the brain and in the recognition that the -- of 20 the importance of those advances. 21 Q. On the day after the election maybe we ought to 22 talk about both parties. You said President Bush declared 23 that; has President Clinton spoken about this subject? 24 A. Yes, he has. I think on more than one occasion, 25 but in -- earlier this year I attended a meeting of the 44 1 International College of Neuropsychopharmacology, which was 2 held in Washington, D.C., and in the opening ceremony of that 3 meeting, Mrs. Gore, Tipper Gore, the wife of our 4 Vice-President, spoke to the attendees at this congress, as 5 you probably know, she has been a very active advocate for the 6 study and treatment of mental illness and for health care in 7 general, and she actually brought and read a letter from 8 President Clinton to that congress, emphasizing again that as 9 we approach the midpoint of this decade of the brain, his 10 personal appreciation for all that neuroscientists had done 11 and his optimism that in the future this knowledge that was 12 being created would be of benefit to all of mankind. 13 Q. All right. Let's turn to the disease of 14 depression itself. Have we seen similar advances in recent 15 times, the last 50 years and more or closer, and have we seen 16 advances in the treatment of depression? 17 A. Yes. We've seen important advances. 18 Q. Just in a nutshell, what types of advances? 19 A. Are you asking specifically about the treatment 20 of depression? Did I understand that correctly? 21 Q. Yes. Yes. 22 A. Well, as I mentioned, in the late 1950s, there 23 was actually the discovery of two kinds of antidepressant 24 drugs, what we call the tricyclic antidepressant drugs and 25 also the monoamine-oxidase-inhibiting antidepressant drugs. 45 1 And those -- before that there really were not good 2 medications for the treatment of depression, and those made a 3 big impact on the treatment of depression. They've been very 4 useful drugs. They have had some limitations principally 5 because of their side effects, and I think most people would 6 point to the introduction of the serotonin uptake inhibitors, 7 of which Prozac was the first one, as the next major advance 8 in the treatment of depression, which happened only a few 9 years ago. 10 Q. How old is the disease of depression? 11 A. The disease undoubtedly is an old disease. It's 12 probably been present throughout recorded history. 13 Q. Many famous individuals have had it? 14 A. That's correct. 15 Q. And everyday folks, as well? 16 A. Yes. 17 Q. Since Lilly has produced the Prozac medicine in 18 the late '80s, have others followed Lilly's lead with the 19 so-called SSRIs or serotonin reuptake medicine? 20 A. Yes, sir; they have. There are a number of 21 different serotonin uptake inhibitors that are now used as 22 drugs or at least three in the United States and there are 23 several others that are used in countries outside the United 24 States and still others that have been shown to be effective 25 in the treatment of depression. 46 1 Q. Now, Doctor, again, turning to another subject, 2 we've had depression throughout human history; we've been able 3 to treat it with medicines for the first time effectively in 4 the latter part of this century. Could you tell the jury how 5 we first learned that medicines, something you could take with 6 your mouth, might help depression and how that led toward 7 further research in the research on Prozac? 8 A. Okay. The two classes of drugs that I mentioned 9 were actually discovered accidentally during the late 1950s. 10 The tricyclic -- the first of the tricyclic drugs was a 11 compound called imipramine and it actually was chemically 12 related to the phenothiazine drugs that I had mentioned and 13 was being studied in humans because of its relationship to 14 those drugs, and it was observed that it seemed to have 15 antidepressant activity in those psychiatric patients who were 16 depressed, they seemed to get better. And that was soon 17 verified in larger controlled studies. So that imipramine was 18 the first of the tricyclic drugs to have been shown to be 19 effective in the treatment of depression. 20 And completely independent of that, another drug 21 called Iproniazid was being studied for the treatment of 22 tuberculosis. It was related chemically to another anti-TB 23 drug. And in the course of doing studies with Iproniazid, the 24 clinical investigators discovered that those tuberculosis 25 patients often were depressed, perhaps understandably, because 47 1 of their illness. And they actually felt better. It didn't 2 necessarily help their TB, but it made them feel better, and 3 so it was discovered to have antidepressant activity. 4 And with the introduction of those two classes 5 of drugs, scientists immediately began to try to understand 6 what is the biochemical action that these drugs have which 7 lead to their antidepressant effects, and it was quickly found 8 that Iproniazid inhibited this enzyme that we mentioned called 9 monoamine oxidase, and so other monoamine oxidase inhibitors 10 were then developed as antidepressant drugs. And their action 11 was thought to be due to their effects on one of the 12 neurotransmitters in the brain called a monoamine, that 13 includes serotonin, norepinephrine and some other transmitters 14 in the brain, as well. And also in the study of the tricyclic 15 drugs, imipramine, it was found a few years later that they 16 inhibited a process called uptake of those same monoamine 17 neurotransmitters. So both classes of drugs seemed to be 18 acting by affecting these particular neurotransmitters in the 19 brain, either norepinephrine or serotonin. 20 Q. Doctor, that's a lack, I'm sure it's a lack of 21 history, but just so we get it straight, on the one hand with 22 the MAOIs, that type of antidepressant, scientists were 23 looking for a way to cure or alleviate TB, tuberculosis? 24 MR. SMITH: Your Honor, at this time, we're 25 going to have to object to the leading nature of the 48 1 questions. 2 JUDGE POTTER: Well, it's preliminary. 3 Go ahead, Mr. McGoldrick. 4 Q. Is that right? 5 A. That is correct. The drug was being developed 6 for the treatment of TB. 7 Q. But it was found to have benefit for something 8 else? 9 A. That's correct; that is, depression. 10 Q. And, similarly, with the tricyclics, they were 11 trying to treat something else, find something else? 12 A. The compound imipramine was being studied 13 because it chemically was related to the phenothiazine drugs, 14 but it was found in the human studies to have quite a separate 15 effect, namely an antidepressant effect. 16 Q. And, again, why was that important, those two 17 findings? Was it just for there being a medicine or was there 18 another reason? 19 A. Well, clearly it was important because it 20 provided new useful medications for the treatment of the 21 disease, but in addition, it was important because once we 22 understood the mechanism or action of those drugs, it helped 23 us understand more about the disease itself and helped us 24 realize that there were specific approaches to the treatment 25 of that disease that provided the opportunity for new kinds of 49 1 medications. 2 Q. And following that, when did we start to learn 3 about anything related to depression in serotonin? 4 A. It was -- certainly that was an important thing 5 we learned, the fact that both classes of antidepressant drugs 6 did affect serotonin, as well as other transmitters. We also 7 learned a great deal about serotonin in relation to depression 8 from studies that were being done by clinical investigators in 9 various parts of the world who actually measured in brain 10 tissue obtained at autopsy from patients who had died, that 11 the results of those studies showed that in patients who had 12 been depressed there often was a lower amount of serotonin in 13 their brain tissue than in patients who had died but who had 14 not been depressed. That also implicated serotonin as being 15 important in depression. 16 Q. Was that work done at Lilly or elsewhere and 17 where was it done? 18 A. No. None of that particular work was done at 19 Lilly. That work was done really in various parts of the 20 world. A lot of the studies I think were done in England and 21 in European countries. 22 Q. And was there any other evidence with respect to 23 the relationship between serotonin and depression at about 24 that time? 25 A. Yes. Overlapping, perhaps coming a little bit 50 1 later than some of that work which involved actual study of 2 brain tissue obtained at autopsy, there also had been -- were 3 a lot of studies done with cerebrospinal fluid obtained by 4 spinal taps from living patients. And those studies, many of 5 them, showed that the concentration in the cerebrospinal 6 fluid, not of serotonin itself but of a serotonin metabolite 7 called 5-hydroxyindoleacetic acid or, abbreviated, 5-HIAA, 8 this metabolite was found to be decreased in the cerebrospinal 9 fluid of many depressed patients. 10 Q. That's a very long word. I'm not going to try 11 to repeat it. We call it 5-HIAA? 12 A. That's correct. 13 Q. And what again is that? 14 A. It is a breakdown product from serotonin so that 15 when there's a reduced amount of 5-HIAA in the cerebrospinal 16 fluid, the interpretation was that serotonin function was 17 decreased in those patients and therefore might be related to 18 their depressive illness. 19 Q. Has that principle, the 5-HIAA being related to 20 serotonin levels, been demonstrated scientifically? 21 A. Yes. Oh, yes, it has. 22 Q. Were the tricyclic and the MAOI type of 23 antidepressants effective to treat depression? 24 A. Both of those classes of drugs were effective in 25 treating depression, yeah, are effective. 51 1 Q. And they still are? 2 A. They still are. 3 Q. Right. Is Prozac more or about the same or less 4 effective than those medicines in treating depression? 5 A. Prozac is very comparable to the tricyclic 6 antidepressant drugs in terms of its efficacy. They are 7 effective in about the same percentage of patients. The major 8 difference between Prozac and those tricyclic drugs relates to 9 the specificity of their pharmacologic action, and that 10 means -- that translates into side effects in clinical use. 11 Prozac has a lot fewer side effects than the earlier tricyclic 12 drugs had. 13 Q. So they both work about the same percentage of 14 time? 15 A. Yes, sir. 16 Q. But the MAOIs and the tricyclics have more side 17 effects? 18 A. Yes, sir. The MAOIs have a particular set of 19 side effects which has limited their use, and the tricyclic 20 drugs have very prominent side effects such as the so-called 21 anticholinergic side effects, which have caused a lot of 22 patients to be unwilling to take those drugs. 23 Q. Yes. Briefly, what kinds of side effects? 24 A. Well, the anticholinergic side effects include 25 things like dry mouth and blurred vision, sometimes 52 1 constipation and that sort of thing. In addition to that, 2 there's a side effect of drowsiness and sedation, which can be 3 a real problem. There's what's called postural hypotension, 4 which is a lowering of blood pressure when you stand up. 5 That's a problem especially in elderly patients because 6 sometimes they fall and break a bone. And there's also the 7 effects of the -- 8 Q. Just so I understand you, postural hypotension? 9 A. Yes, sir. 10 Q. That's not hypertension like high blood 11 pressure? 12 A. It's a low blood pressure. The blood pressure 13 falls when people stand up. 14 Q. If I go down here and come up real fast my head 15 might get light? 16 A. Yes, sir. And you might fall down. 17 Q. I might do that anyway. But, in any event, in 18 these people the medicine might cause that? 19 A. That's correct. 20 Q. What about this side effect you get with the 21 tricyclics and the MAOIs that involves tiring? Tell the jury 22 about that. 23 A. Yes. That's the particular concern with 24 monoamine oxidase inhibitors. There's a substance called 25 tyramine, which is a monoamine and which ordinarily it can be 53 1 present in some of the foods that we eat, particularly in 2 fermented foods like beer and wine and some types of ripe 3 cheeses and that sort of thing. Ordinarily when we eat 4 tyramine it's rapidly destroyed in our liver and never gets 5 into our circulation, but in patients who are taking monoamine 6 oxidase inhibitors, the breakdown of that tyramine is 7 prevented, so that if they eat these kinds of foods, that 8 tyramine can actually cause very severe reactions, in this 9 case an increase in blood pressure, and actually sometimes 10 deaths have occurred in patients on MAO inhibitors who ate 11 these kinds of food. 12 Q. So people taking those medicines have to be real 13 careful about what they eat? 14 A. Yes, sir. 15 Q. Now, why did these disadvantages occur in these 16 MAOI and tricyclic medicines? What is it that's making them 17 do that? 18 A. Well, they occur because of the actions of those 19 drugs. In the case of the MAO inhibitors, the reason they 20 help depression is believed to be that they inhibit the 21 degradation of serotonin and norepinephrine. The reason they 22 cause side effects is that they also inhibit the degradation 23 of this substance tyramine. 24 In the case of the tricyclic drugs, again, the 25 reason they help depression is because they block the uptake 54 1 of serotonin and norepinephrine, and the reason they cause all 2 these side effects is because they have other pharmacologic 3 actions. They block cholinergic receptors, they block 4 histamine receptors, they block adrenergic receptors and they 5 have direct effects on the heart. 6 Q. Did this lead scientists to look for more 7 selective medicines? 8 A. Yes, sir. The idea was to retain only the 9 desirable actions of those drugs and get rid of those other 10 actions which only caused side effects. 11 Q. And what was one way people were looking at that 12 when you started at Lilly? 13 A. When I started at Lilly, there were -- well, 14 again, one of the classes of drugs that I worked on at the 15 beginning at Lilly was a group of monoamine oxidase inhibitors 16 and we were particularly working on a group of compounds that 17 were selective in blocking the only one form of monoamine 18 oxidase, what we now call MAO Type A, and they didn't affect 19 MAO Type B, and so our objective was to find drugs that had 20 the desirable therapeutic effect but didn't have the side 21 effects. 22 Q. And did that eventually lead you to look at 23 serotonin? 24 A. We were focusing on serotonin because we 25 believed it to be a transmitter that was important in 55 1 depression and in the action of those antidepressant drugs. 2 Q. And that is around -- we've gotten the science 3 to around the time you come to Lilly; is that right? 4 A. Yes, sir. 5 Q. And that's in what period on the calendar? 6 A. I joined Lilly in 1963. 7 Q. All right. And we'll return to how you folks at 8 Lilly dealt with that, but if I can, I'd like to take just a 9 minute or two and address for the jury some very basic -- for 10 you, but not for the rest of us -- terms that neuroscientists 11 deal with. First of all, what is neuroscience? 12 A. Well, neuroscience is basically the study of 13 neurons, which are nerves, the study of nerve functions. Most 14 neuroscience concerns the brain, which is the largest single 15 collection of nerves within our body. 16 Q. And this is a real big topic and not everybody 17 knows all the answers, but how does the brain work? Basically 18 how does it work? 19 A. Well, fundamentally, the brain is a big 20 collection of individual nerve cells or neurons. It's 21 estimated that in the human brain there's more than 10 billion 22 neurons and these are -- 23 Q. That's 10 billion? 24 A. Ten billion, yes, more than 10 billion. These 25 are connected together in very complicated ways, but each 56 1 neuron is sending messages or signals to a lot of other 2 neurons and is receiving signals or messages from again many 3 different neurons, so it's an extraordinarily complicated 4 network of communication. 5 Q. What is a neuron? 6 A. A neuron is an individual nerve cell. 7 Q. What is a neurotransmitter? 8 A. Well, the way these neurons communicate with 9 each other is by releasing a particular substance called a 10 neurotransmitter. One individual neuron releases a 11 neurotransmitter which then acts on the target neuron to cause 12 it to do something. It has been preprogrammed to respond to 13 particular neurotransmitters in a particular way. And so 14 basically the way these neurons communicate is by releasing 15 these substances called neurotransmitters. They transmit the 16 nerve signal from one nerve to the next one. 17 Q. A neurotransmitter in kind of a way carries a 18 message? 19 A. That's exactly what they do, yes. 20 Q. It might be thought of as a smoke signal or 21 something like that in very, very common terms? 22 A. That used to be a way of sending messages, yes. 23 Q. All right. What is reuptake? 24 A. Well, these neurotransmitters, once they have 25 transmitted the message from the sending neuron to the 57 1 receiving neuron, they need to be inactivated some way, gotten 2 rid of, and one of the important ways that this often is done 3 is by a process called reuptake, which simply means that the 4 sending neuron, not only releases the transmitter but when it 5 has done its job it actually takes it back up, it sucks it 6 back up to inactivate it and get it out of this synaptic 7 cleft, which is the area between the two neurons. 8 Q. And what is serotonin? I think you've told us 9 but... 10 A. Well, serotonin chemically is 11 5-hydroxytryptamine. It is simply one of the brain's 12 neurotransmitters. There's dozens or hundreds of them, some 13 that haven't yet been discovered, I'm sure. But serotonin is 14 one of the neurotransmitters in the brain. 15 Q. Now, again, very briefly and we'll come back to 16 some of this later, what do we know about the relationship 17 between serotonin and depression now today? 18 A. Well, there's a great deal of evidence that 19 suggests that depression may be caused by a deficiency of 20 serotonin in the brain. 21 Q. And what kind of evidence is that, Doctor? 22 A. It includes the kinds of studies that I talked 23 about where lower amounts of serotonin have been found in 24 brain tissue obtained at autopsy. 25 Q. Let me just stop you there. That's work done 58 1 where, all over the world? 2 A. All over the world, basically in Europe and in 3 England. 4 Q. That was Number One. What's next? 5 A. The second of the studies that I mentioned that 6 that involved measuring in the cerebrospinal fluid of living 7 patients the amount of this serotonin metabolite called 8 5-HIAA. 9 Q. And where was that work done? 10 A. That work has been done a lot of different 11 places in various medical centers in the United States. Some 12 of the early pioneering work was actually done in Sweden by 13 Doctor Marie Asberg and some of her co-workers at I believe 14 the Karolinska Institute. 15 Q. And approximately when was that work done, very 16 roughly? 17 A. The work probably began in the late 1960s. I 18 remember specifically discussing of it at a meeting in 1972. 19 It was happening during that time and it has continued since 20 then. 21 Q. Any other evidence to support this relationship 22 between serotonin and depression? 23 A. Well, a very major part of the work then has 24 also been the study of the mechanism of action of those 25 antidepressant drugs, both the monoamine oxidase inhibitors 59 1 and the tricyclic drugs. It's been shown that they affect 2 serotonin. They increase serotonin amount or serotonin 3 function, and so that also was part of the evidence that told 4 us that serotonin is important in depression. 5 Q. Is that true of Prozac and the other SSRIs, as 6 well? 7 A. Yes. The unique thing about Prozac is that it 8 also affects serotonin, but it only affects serotonin; 9 whereas, those other drugs affected not only serotonin but 10 other neurotransmitters, as well. 11 Q. So let me understand it. The evidence of the 12 relationship between serotonin and depression, this evidence 13 you're talking about is that these medicines that we know work 14 on depression we also know affect serotonin? 15 A. That's correct. And when Prozac was first 16 developed -- in fact, one of the major benefits of being able 17 to study that compound in humans was that we would learn now 18 something new: Is serotonin as important in depression as we 19 thought. 20 Q. What did we learn? 21 A. We learned that the drug was effective and now 22 that other serotonin uptake inhibitors also are effective, 23 therefore serotonin is indeed important in depression. 24 Q. And is there some other recent work that relates 25 to the serotonin and depression? 60 1 A. Well, there continues to be a lot of 2 investigation of serotonin in depression. Again, the 3 methodology that is available now keeps improving so that we 4 can measure different things. People are trying to measure 5 various components of serotonin function in humans using 6 techniques like imaging techniques, which allow one to see 7 what is going on inside the brain of a living person, and some 8 of those studies have involved measuring serotonin receptors. 9 There are some reports that there have changes in those 10 receptors in depressed patients. So the evidence linking 11 serotonin and depression I think is continuing to build. 12 Q. Has there -- some work been done at Yale? 13 A. Yes. The work I think you're referring to was 14 done by Professor Dennis Charney and his colleagues at Yale 15 University Medical School. They have used a mixture of amino 16 acids in the form of a little drink, and normally proteins 17 contain about 20 or more different amino acids. One of those 18 is tryptophan, which is actually the substance from which 19 serotonin is formed. What the group at Yale has done is to 20 give people a mixture of amino acids lacking one amino acid, 21 namely tryptophan. And when people drink this, these other 22 amino acids keep the tryptophan from entering into the brain 23 and it actually temporarily interrupts serotonin synthesis. 24 So the study that they did was to take depressed 25 patients who had responded to an antidepressant drug and now 61 1 were better, and give them this mixture of amino acids to stop 2 serotonin synthesis. If the serotonin was important to the 3 action of those drugs, they expected those patients to 4 temporarily become worse, and that's exactly what happened. 5 Those patients, their depressive symptoms recurred. That 6 happened when they were getting a drug like Prozac or one of 7 the tricyclic drugs which affected serotonin, but it didn't 8 happen when they were getting a drug that was very specific 9 and affecting just norepinephrine. So those studies have 10 really proven that serotonin is indeed important to the action 11 of drugs like Prozac and other less specific drugs, as well. 12 Q. You're familiar with the medical literature and 13 the thinking of scientists in this area. Is what you've just 14 told us, the relationship between serotonin and depression 15 widely accepted in the scientific community? 16 A. Yes. I think -- I think it certainly is. I 17 think even the fact that so many different selective serotonin 18 uptake inhibitors are now available and have been studied, 19 compounds which are very pure in their pharmacologic action, 20 that in itself was pretty compelling evidence that serotonin 21 was important in depression, and I think the studies that the 22 Yale group has done has simply established that further. And 23 I think most psychiatrists and neuroscientists feel that that 24 is a very compelling body of evidence to link serotonin with 25 depression. 62 1 Q. So if someone came in here and suggested the 2 contrary to this jury, that would not be the mainstream of 3 science? 4 A. That would be exactly contrary to what most 5 neuroscientists and neuropharmacologists accept and believe. 6 Q. Your Honor, if this were an appropriate time for 7 a mid-morning break, I'd like to take it. 8 JUDGE POTTER: Ladies and gentlemen, we'll take 9 the morning recess. As I mentioned to you-all before, do not 10 communicate with anybody about this case; do not discuss it 11 among yourselves or form or express opinions. We'll take a 12 15-minute recess. 13 (RECESS) 14 SHERIFF CECIL: The jury is now entering. All 15 jurors are present. Court is back in session. 16 JUDGE POTTER: Please be seated. 17 Doctor, I'll remind you you're still under oath. 18 Mr. McGoldrick. 19 MR. McGOLDRICK: Thank you. 20 Doctor Fuller, before the break, we were talking 21 about the relationship between serotonin levels and 22 depression, and you were giving the jury the evidence for that 23 relationship. Now I'd like to turn to another subject, which 24 is your testimony about the relationship between Prozac and 25 serotonin levels and how that works. And I'd first of all 63 1 like you to tell the jury, in words, how does it work in a 2 nutshell. 3 A. Well, what Prozac does is to inhibit the uptake 4 of serotonin. Remember, that uptake is a way of inactivating 5 the serotonin, so it is blocking the inactivation of serotonin 6 that has been released from one neuron to have an effect on 7 the target neuron. So that means that if the inactivation is 8 blocked, the effect of that serotonin is bigger than it would 9 have been otherwise. Fluoxetine, or Prozac, essentially 10 magnifies serotonin signals as they are sent from serotonin 11 neurons to target neurons. 12 Q. And what's the idea of that? Why is that a good 13 thing? 14 A. Well, if depressive illness is caused by too 15 little serotonin function, this is a way of increasing that 16 serotonin function back up to where it ought to be. 17 Q. Now, Doctor, we've put together a couple of 18 boards here, displays, which I ask you if they would help you 19 explain this system to the jury. 20 A. I think they would, because they actually depict 21 what events that are going on that I have mentioned here. 22 Q. Okay. I'd ask you then if you would come down 23 here to this easel and we'll see how this works, if we can get 24 it to work, and if the jury can't see I hope they'll let 25 somebody know. 64 1 All right. We've got a -- we'll take a board 2 here and I'll put it up, and I'll ask you, Doctor Fuller, to 3 explain to the jury what that shows. 4 Before you start, let me just show Your Honor. 5 JUDGE POTTER: Go ahead. 6 Q. He doesn't want to see it. All right. Doctor 7 Fuller, tell us what this is designed to represent and what 8 all this is. 9 A. Well, this is just a drawing, of course, not a 10 photomicrograph or something, but it's intended to represent, 11 over here, the ending of a serotonin neuron that in some part 12 of the brain is making contact, input, to this one. 13 Neuroanatomically what this would look like is that this nerve 14 cell is actually very close to this nerve cell. The artist 15 has pulled them apart so that you can see what is going on in 16 here, just to help you see, but they would ordinarily be very 17 close together. 18 So what this neuron is doing is that it is 19 making serotonin and is storing it here in the nerve ending, 20 and then when it is ready to send a signal to this neuron, it 21 actually releases some of that serotonin. This little yellow 22 ball is intended to be a serotonin molecule. And so that 23 serotonin is released from this neuron, and it comes into 24 contact then with this neuron and, in particular, there are 25 specific receptor sites here that recognize a serotonin 65 1 molecule. So when serotonin is released from this neuron and 2 comes in contact with one of these receptor sites, it triggers 3 some response in that neuron. 4 Q. Would this help to show that response? 5 A. Yes. This is simply the same drawing, except 6 now you see that this serotonin molecule has come into contact 7 with one of these receptors, and this receptor -- this neuron 8 is programmed ahead of time to know that when it is signaled 9 by a serotonin molecule, it needs to do something; that 10 something can be different things in different parts of the 11 brain, but it is responding, the little light here is just to 12 indicate that the neuron is responding to this serotonin 13 signal that has been sent from this serotonin neuron. 14 Q. Now, Doctor, before you go on, let me just ask 15 you a couple of questions. You referred to these receptor 16 sites over here, these little round holes as we've got in the 17 drawing, as specific. What does that mean? 18 A. Well, that means they wouldn't respond to 19 anything else, to any other neurotransmitters, for example. 20 If there were norepinephrine nerves out here that were 21 releasing norepinephrine, and one of those norepinephrine 22 molecules came into contact with this receptor, nothing would 23 happen. These receptors are there to specifically recognize 24 serotonin. There would be separate receptors that would 25 recognize norepinephrine or other neurotransmitters, but 66 1 these receptors are very specific in just recognizing 2 serotonin. 3 Q. So that if this is round and this is round, they 4 fit and they can specifically go, but if it were square or 5 some other shape and it came out, it wouldn't fit in there? 6 A. That's correct. 7 Q. Is that how it really is in the body, with 8 circles and squares, or is it chemicals are different? 9 A. Well, chemicals have a shape to the molecule; 10 they wouldn't be perfectly round, but each chemical molecule 11 has a unique shape, so the receptor would recognize that shape 12 and the nature of that particular molecule. 13 Q. All right. Maybe we can go to the next board 14 and we can continue the process. What is this board designed 15 to -- I tell you what. Before I ask you that, obviously this 16 is a blowup? 17 A. Yes. 18 Q. Is it many, many, many, many times? 19 A. That's correct. An individual neuron you would 20 not be able to see without the aid of a microscope. 21 Q. Could you see it with the aid of a microscope? 22 A. Oh, yes. 23 Q. Can you see some of these functions with 24 electron microscopes and so forth? 25 A. Yes. In fact, this drawing is based upon what 67 1 we know to exist. You can actually see nerve terminals. You 2 can see these little storage granules or vesicles within them. 3 You wouldn't be able to see in a microscope a particular 4 receptor, but you could actually add a radioactive substance 5 which would attach to these receptors, and then using a 6 technique called autoradiography, you could actually localize 7 where those receptors are on target neurons. So one way or 8 another it's possible to measure all those constituents that 9 are shown here. 10 Q. Just so we understand, then in radioactivity, 11 you're talking about, you use that really just to label, to 12 mark certain kinds of chemicals so you can test them and see 13 where they are with Geiger counters? 14 A. Yes. That's the idea. 15 Q. If this were -- these are nerve endings? 16 A. Yes. 17 Q. This is the ending of a nerve cell? 18 A. Yes. That's correct. 19 Q. How far does the nerve go, next county or... 20 A. Well, if it's gone in proportion to this scale, 21 the rest of the nerve would go outside that door and I'm not 22 sure how far, but this just represents just the end of a nerve 23 that's coming in from some part of the brain to make contact 24 here. 25 Q. And while we're at it, you called this what? 68 1 A. These are called granules or vesicles. They 2 look like little granules within the nerve cell. Again, they 3 can be seen with microscopic techniques. 4 Q. And what is their function? 5 A. Their function is simply to store serotonin. 6 There would be a lot of serotonin molecules stored in here, 7 and then when this serotonin nerve is ready to send a signal 8 to this target neuron, it would release some of those 9 serotonin molecules out of these granules into this space. 10 This is the space that I mentioned, which is called a synaptic 11 cleft or a synaptic gap, because this nerve connection is 12 called a synapse. 13 Q. And, Doctor, I think in the first board that's 14 behind here we showed a serotonin molecule coming out. Then 15 you just told the jury this is -- 16 A. It acts on the receptor; it causes this neuron 17 to do something, and that sort of completes the process of 18 neurotransmission. This neuron has sent a signal to this 19 neuron and it has responded. That's the process of 20 neurotransmission. 21 Q. Then what happens next, sir? 22 A. What happens then is that this serotonin 23 molecule needs to be removed, and the way it is removed is 24 through the action of what I may have referred to as a 25 transporter or a pump. It's a part of the cell membrane here, 69 1 which again has a spot on it that recognizes serotonin. And 2 when a serotonin molecule combines with that, it pumps that 3 serotonin molecule back inside this neuron and now it's no 4 longer in contact with this target neuron, so its action has 5 been terminated through this process of uptake or reuptake. 6 Q. Sends it out, does its job, pulls it back in? 7 A. That's correct. 8 Q. What happens to it once it is pulled back in? 9 A. Once it goes back inside this nerve cell, it can 10 be reused in these storage granules or sometimes it's 11 destroyed enzymatically by the action of this enzyme that I 12 mentioned called monoamine oxidase. 13 Q. All right. And let's go to the next board and 14 see if we can continue the process and explain it. Take this 15 down. What's this one, Doctor? 16 A. Well, this is all the same structures, except 17 now the red structure here is intended to represent the action 18 of Prozac, or fluoxetine, or some other serotonin uptake 19 inhibitor which acts in that same way. And you'll see what it 20 does is combine with this transporter, or pump, but it is not 21 taken inside the cell by that pump, it simply occupies it so 22 that it can no longer take up serotonin. 23 So this uptake process, which is the way 24 serotonin is inactivated by being pumped out of the synaptic 25 cleft is now blocked. And so the serotonin molecules that 70 1 were released out here are still out here to be acting on that 2 receptor. And I think the next slide will actually show, if 3 I'm not mistaken -- yes -- that as a result of blocking this 4 uptake carrier, then when serotonin molecules are released, as 5 I mentioned, they are no longer able to be taken up, so there 6 are more of them present out here in the synaptic cleft, more 7 of them acting on these receptors. That's why I used the term 8 that the signals are magnified or amplified by blocking this 9 uptake. Whatever signals serotonin neurons send are now 10 stronger than they were before uptake was inhibited. 11 Q. Doctor, let me ask you a couple of questions. 12 This medicine, Prozac, that blocks the uptake pump, Lilly 13 makes that? 14 A. Yes, sir. 15 Q. Are there other medicines that act in the same 16 way? 17 A. Yes, there are. There are other medicines. And 18 I mentioned earlier that the tricyclic drugs, some of the 19 drugs like imipramine actually do this, they just do a lot of 20 other things in addition to that. The unique thing about 21 Prozac is that it only blocked the uptake of serotonin, it 22 didn't block the uptake of norepinephrine, it doesn't block 23 various receptors that I mentioned, cholinergic receptors and 24 histamine receptors, which would be located over here on other 25 neurons. It doesn't have all of those actions; it only is 71 1 blocking the uptake of this serotonin transporter. 2 Q. Now, since Lilly first came out with Prozac, the 3 first of these selective reuptake inhibitors, have other 4 companies made similar reuptake inhibitors? 5 A. Yes, sir. There are quite a number now of other 6 selective serotonin uptake inhibitors that are known, 7 compounds, including zimelidine, puroxetine, sertraline, 8 indalpine, citalopram and others, several others. 9 Q. What other companies makes these? 10 A. In the United States, SmithKline-Beecham makes 11 puroxetine and Pfizer makes sertraline. 12 Q. And those were after Lilly first discovered and 13 you discovered Prozac? 14 A. Yes, sir. Yes, sir. 15 Q. Now, let me ask you another question. If you've 16 got this cell sending out serotonin, which we represented as 17 the little yellow balls, and you've got the fluoxetine that's 18 Prozac blocking the reuptake, you get more of the serotonin in 19 the synapse? 20 A. Yes. 21 Q. Once again, why is that good? 22 A. Well, because you're magnifying these serotonin 23 signals. You're increasing the effectiveness of the serotonin 24 neurons in sending those signals. 25 Q. And is that good in the depressed patient? 72 1 A. That seems to be the basis for the improvement 2 in depressed patients, the alleviation of depressive symptoms. 3 Q. And why don't we get -- strike that. 4 Do we get just a huge amount of these yellow 5 balls keep coming out and none of them being taken up and this 6 is nothing but yellow balls in here? 7 A. Let me emphasize again that, for simplicity, 8 most of these just show one serotonin molecule. Obviously 9 there are many serotonin molecules being released at one time, 10 not just one. But the principle is that there's an increased 11 amount of serotonin out here in the synaptic cleft after 12 uptake is inhibited and, therefore, this signaling by these 13 serotonin neurons is increased. It's actually possible -- I 14 mentioned that many of these things can be measured. It's 15 actually possible to measure the concentration of serotonin 16 out here in the extracellular fluid. This is done by a 17 technique called brain microdialysis. It can be done in 18 laboratory animals; it could be done in humans except that it 19 involves implanting a small microdialysis fiber into some part 20 of the brain, so this would not be done in humans. But the 21 principle, the technique could be done in any animals. 22 We actually do this in my laboratory in 23 laboratory rats, and we can actually measure the concentration 24 of serotonin in the extracellular fluid. And when we do that 25 and we administer fluoxetine to those rats, we measure a 73 1 marked increase in the amount of serotonin in the 2 extracellular fluid. This occurs within minutes after giving 3 fluoxetine, and the increase in serotonin lasts for as long as 4 uptake is inhibited by fluoxetine. So we typically measure, 5 say, a three- to fivefold increase in the amount of serotonin 6 in the extracellular fluid after giving fluoxetine. 7 Q. And, Doctor, could you explain to the jury why 8 the concentration of serotonin, the number of molecules or 9 yellow balls that we have here, doesn't just keep going up and 10 up and up and up, or does it? 11 A. No, it doesn't. And the reason it doesn't, 12 there's another component here which I really haven't pointed 13 to yet. In addition to the receptors that are located on this 14 target neuron that recognize serotonin, another part that 15 recognizes serotonin here, called the transporter, there are 16 also receptors located here on the serotonin nerves themselves 17 which recognize serotonin. And the purpose of these 18 receptors, which are called autoreceptors because they are on 19 the serotonin nerves themselves, the purpose of those 20 receptors is to sense or monitor the concentration of 21 serotonin in the extracellular fluid, so that when this 22 receptor is contacted by serotonin molecules frequently, it 23 senses that there's an increased number of serotonin molecules 24 out there; I'm going to slow down my firing and release of 25 serotonin because there's already enough out there. 74 1 So if you measure electrophysiologically the 2 rate at which serotonin nerves fire, what you find is that 3 that goes down when fluoxetine is given, the neurons slow 4 down. If you measure neurochemically the rate at which 5 serotonin is being made and released, that goes down when 6 fluoxetine is given, so that as serotonin begins to accumulate 7 here in the synaptic cleft, the neuron says, "I don't need to 8 be putting out any more serotonin; I'm going to slow down." 9 And so the serotonin accumulates here only up to a certain 10 level and not any further, and that is an important control 11 mechanism probably that limits any side effects that are 12 associated with drugs of this sort, because the neuron is in 13 control in terms of how much it is going to let you increase 14 serotonin signaling or magnify those serotonin signals. 15 There are other kinds of drugs, as a matter of 16 fact, which release serotonin independently of whether the 17 neuron wants it released or not, whether the neuron is firing. 18 Those kinds of drugs can cause much larger increases of 19 serotonin here. But serotonin uptake inhibitors only cause a 20 limited increase in this extracellular serotonin. 21 Q. Has that been scientifically studied and proven? 22 A. It's been shown, again, through this technique 23 of microdialysis, as well as through other techniques, but 24 perhaps most dramatically through this technique of 25 microdialysis by a number of investigators, yes. 75 1 Q. So the amount of serotonin that -- in the 2 synaptic cleft caused by this medicine doesn't just go up and 3 up and up, it's limited in some self-regulating way? 4 A. That's correct. 5 Q. Is self-regulating mechanism of that sort common 6 in body systems in all the ways we work? 7 A. Yes. It's very common. That's how our bodies 8 stay as, quote, normal as they are, in that there are a lot of 9 controlled mechanisms like this involving autoreceptors or 10 controlling mechanisms, such that when there's more serotonin 11 out here, the neuron slows down. That's what these sensing 12 devices are for, is to maintain the proper level of 13 transmission in this case. 14 Q. Now, I believe there has been some testimony in 15 this case by, I believe it was Doctor Breggin, the jury will 16 remember it, that this just keeps going up, the amount of 17 serotonin gets jacked up and stays up. 18 MR. SMITH: We'd object to that as a 19 mischaracterization of what Doctor Breggin said, Your Honor. 20 JUDGE POTTER: I'm going to sustain it. 21 Q. We can go to the transcript if it helps, but why 22 don't we just answer the question. Does that serotonin system 23 keep going up and get out of control? 24 A. No. Again, the effect of uptake inhibitors is 25 limited by the extent to which the neurons are releasing 76 1 serotonin. So the neuron itself is ultimately in control of 2 how much it will allow you to increase the signals that it's 3 sending as a result of uptake inhibition. 4 Q. All right. And, now, you've indicated that by 5 this autoreceptor mechanism, this neuron slows down its 6 production of serotonin. 7 A. That's correct. 8 Q. Why don't we then get too little -- or do we get 9 too little serotonin in the synaptic cleft? 10 A. No. We don't, because, again, the reason this 11 neuron is slowing down is because it is aware that there is an 12 increased amount of serotonin out here. If there wasn't an 13 increased amount of serotonin out here, it wouldn't be slowing 14 down. So as a result of uptake inhibition, there is an 15 increase in the amount of extracellular serotonin; it's just 16 that that increase is limited by the neuron itself, only 17 allowing you to increase it up to a certain point. 18 Q. Now, I believe Doctor Breggin did testify that 19 the effect of fluoxetine, Prozac, can be to cause this neuron 20 to shut down. Is that correct? 21 A. No. That is not correct. The neuron does not 22 shut down. What the neuron does, again, is respond to the 23 amount of serotonin that's out here in the synaptic cleft. As 24 a result of uptake inhibition, when this increases, the neuron 25 is aware of that increase and it limits the increase by 77 1 slowing down to whatever extent is necessary for this increase 2 not to become excessive. In fact, some work published by 3 Professor Sidney Auerbach at Rutgers University, using this 4 technique that I've mentioned of microdialysis, has shown very 5 clearly that when fluoxetine is given, this increased amount 6 of serotonin persists throughout the period of time that 7 uptake is blocked; and in the case of fluoxetine in the rat, 8 that is more than 24 hours. 9 So the neuron is still firing, making, releasing 10 serotonin throughout all that time, sufficient that the 11 extracellular serotonin is increased, again about three- to 12 fivefold, something in that range. It isn't increased beyond 13 that because the neuron has slowed down, but if the neuron had 14 shut down and wasn't working anymore, of course, that increase 15 couldn't be maintained. In fact, that has been shown 16 experimentally by Lilly investigators, that if they give 17 another drug, which does shut down that neuron then these 18 extracellular serotonin levels fall back to normal. But with 19 fluoxetine, they maintained at that increased concentration 20 for the duration of block of the uptake carrier. 21 Q. So if you use Prozac, does or does not this 22 neuron get shut down? 23 A. It does not get shut down. The neuron responds 24 to the increased amount of serotonin by limiting that increase 25 through its control of the release of serotonin. 78 1 Q. This is a complicated system; there are lots of 2 effects? 3 A. That's correct. 4 Q. The net effect of all of these things on 5 serotonin is what? 6 A. Well, the net effect is to increase serotonin 7 transmission, to increase the transmission of nerve signals 8 that are being sent by serotonin. I've read part of Doctor 9 Breggin's testimony, and he, I think, misused words like 10 transmission versus activity, or maybe misunderstood them. 11 The terms as they are ordinarily used, the activity of the 12 serotonin neuron itself may be slowed down, but the 13 transmission of nerve impulses is increased due to the 14 increased amount of serotonin. 15 MR. SMITH: Your Honor, we'd object to the 16 mischaracterization of Doctor Breggin's testimony. 17 JUDGE POTTER: Well, I don't think -- he's 18 giving his own talk, not mischaracterizing Doctor Breggin. 19 Go ahead, sir. 20 A. My only point was that the activity of the 21 serotonin neuron itself is different than the transmission of 22 signals across this pathway. There's an increased 23 transmission of signals. The extent of that increase is 24 limited because the activity of the serotonin neuron itself is 25 decreased. 79 1 Q. And that effect, then? 2 A. Is an increase in transmission of signals. 3 Q. Let me just ask you a couple things. In the 4 real world -- this is a simplification, in the real world of 5 the neuron and the synapse, you'd have many different reuptake 6 pumps, not just one? 7 A. That's correct. 8 Q. Many different vesicles? 9 A. That's correct. 10 Q. Many different receptors? 11 A. Yes, sir. 12 Q. This is just to simplify it to show how it 13 works? 14 A. Yes, sir. 15 Q. I think that's all I need of the boards. Why 16 don't you stay here one second if I may, if that's all right 17 with the Court, maybe just go out there and I'll see if I have 18 any more questions. Now, all of these things that you've been 19 describing, is this theoretical or has this been shown and 20 proven by experimental work on animals and others? 21 A. Well, this has all been shown in a variety of 22 ways in experimental work in animals. Again, the kinds of 23 experiments that often are involved could not be done in 24 humans, but just about every process that I mentioned can and 25 has been measured by various methods in laboratory animals. 80 1 Q. In persons, in humans, have there been extensive 2 clinical trials to see if serotonin does work to help 3 alleviate depression? 4 A. The kinds of studies that have verified that 5 have again involved the use of specific drugs, like serotonin 6 uptake inhibitors. They've involved the use of the amino 7 acids which are converted to serotonin; those can alleviate 8 depressive symptoms as well. And they have also included the 9 studies that I mentioned earlier from the group at Yale 10 showing that in patients who have improved, if now you stop 11 serotonin synthesis by giving this tryptophan-free drink, then 12 you terminate the therapeutic effect of those antidepressant 13 drugs. 14 Q. In persons who have depression and who are given 15 Prozac, approximately how many out of 100 would be helped by 16 the medicine? 17 A. Well, typically about 70 percent of the 18 patients, in other words, about 70 out of 100 patients would 19 respond to a drug like Prozac. 20 Q. Is that similar to the percentage that would 21 respond to some of the other drugs? 22 A. Yes, sir. It's just about the same. 23 Q. Now, you've talked about the symptoms of the 24 other drugs being greater -- excuse me, the side effects of 25 the other drugs being greater. How does that translate into 81 1 this molecular world? 2 A. Well, there's a couple of things involved. One 3 is that the tricyclic drugs not only inhibit this serotonin 4 uptake carrier or transporter but they also inhibit the 5 transport of norepinephrine, an additional neurotransmitter. 6 Beyond that, what is particularly important to their side 7 effects is that they not only combine with these transporters, 8 but they also combine them with a whole variety of receptors 9 for neurotransmitters. And the ones in particular that are 10 important to the side effects of those tricyclic drugs are 11 three that I mentioned before: One is the cholinergic 12 receptor, a receptor for the transmitter acetycholine, and 13 when that receptor is blocked by the tricyclic drugs, there's 14 a whole set of side effects that result. And I mentioned that 15 some of those are dry mouth, blurred vision and so on. These 16 are uncomfortable side effects that many patients don't like. 17 They are not life-threatening kinds of side effects. There 18 are also other side effects due to the block of a different 19 receptor called the histamine H-1 receptor, and that results 20 in drowsiness, for example, or sedation, which is why patients 21 who take tricyclic drugs are warned not to operate heavy 22 machinery and that sort of thing. The third receptors that I 23 mentioned are alpha adrenergic receptors, still different 24 receptors on** other neurons, and the block of those receptors 25 causes this side effect of postural hypotension, the drop in 82 1 blood pressure suddenly which can be really dangerous in older 2 patients. And then in addition to those effects on receptors 3 and other transporters, the tricyclic drugs have direct 4 effects on the heart to modify the electrocardiogram. 5 Q. Doctor, from your knowledge of the disease 6 depression, is suicide a problem with that disease? 7 A. Suicide is a very serious problem with 8 depression, yes. 9 Q. Significant numbers of people with depression? 10 A. There are different estimates that people 11 report, but usually something in the neighborhood of 15 12 percent of depressed people are said to commit suicide at some 13 point. 14 Q. Now, is one of the ways people commit suicide by 15 overdosing on their medication or on some medications? 16 A. That in the past has been a very common way. 17 With the tricyclic drugs because of those other effects, they 18 are toxic in overdose so that it has always been possible for 19 patients who were suicidal to actually commit suicide by 20 overdosing with the very drug that had been given to them to 21 treat their depressive illness. That was one of the 22 unfortunate problems with the tricyclic drugs. And indeed one 23 of the advantages of Prozac is that it seems to be very much 24 safer in overdose so that it is not easy for a person to kill 25 himself or herself by overdosing with Prozac. 83 1 Q. How difficult is it? Can you give us some sort 2 of sense? 3 A. Well, I think the evidence is that it's nigh on 4 to impossible that people have tried by taking very large 5 doses of Prozac without it being fatal. One complication, of 6 course is, that many times people swallow a variety of drugs, 7 not just one. 8 Q. What is the characteristic of -- again at the 9 molecular level you've been talking about -- of Prozac that 10 makes it safe in overdose compared to the tricyclics which are 11 dangerous in overdose? 12 A. Well, it relates presumably to the fact that the 13 molecular action of Prozac is very specifically to block 14 serotonin function. It doesn't interact with any of those 15 other targets that I mentioned the tricyclic drugs having. It 16 doesn't block norepinephrine uptake, it doesn't block 17 cholinergic receptors, it doesn't block histamine receptors, 18 it doesn't block adrenergic receptors, and it doesn't have 19 these direct effects on the heart. 20 Q. Now, Doctor, did we with your cooperation -- 21 strike that. 22 This system is not a static system of a bunch of 23 snapshot pictures like this; is that right? 24 A. That's correct. These are actually photographs 25 made from a videotape, which shows all of these events 84 1 actually taking place. 2 Q. There's movement over time in these systems? 3 A. That's right. The serotonin molecule, remember, 4 was released here, it's taken up here and so on. 5 Q. And we with your assistance put together a 6 videotape which demonstrates the dynamic, kinetic effect of 7 the movement of this whole system; is that right? 8 A. Yes, sir; that's right. 9 Q. Have you watched the video? 10 A. Yes, I have. 11 Q. Did you help us prepare it? 12 A. Yes, I did. 13 Q. Did you review it for scientific accuracy? 14 A. Yes, I did. 15 Q. Does the video in a simplified manner accurately 16 explain scientific principles? 17 A. Yes. I think the word simplified needs to be 18 emphasized because, again, it's showing like one molecule of 19 serotonin being released at a time, it's showing the nerves 20 further apart than they actualy would be, but it's all going 21 to illustrate in an easy-to-understand way the events that are 22 going on in a serotonin synapse. 23 Q. Does it accurately portray, to your 24 understanding, of how Prozac works? 25 A. Yes, it does. 85 1 Q. Would showing that video, you think, help 2 explain your testimony to the jury? 3 A. I think it would because you can actually see 4 these things happen. 5 MR. McGOLDRICK: Your Honor, I would like to 6 offer the video and ask that it be published to the jury by 7 means of showing it. 8 JUDGE POTTER: Okay. Certainly. 9 MR. McGOLDRICK: We have to move a little bit of 10 machinery around here, I think. 11 JUDGE POTTER: Ladies and gentlemen, while 12 they're doing that, let me just mention one thing to you and 13 it was highlighted there. Mr. McGoldrick was showing you 14 something and I said it wasn't necessary that I see it. I 15 want to emphasize a couple of things. One, my role in this 16 trial is entirely different from yours. Okay? And so some 17 things that are very, very important for you are not that 18 important for me. Okay? So I don't want anybody to draw any 19 implications that because I'm not looking at something while 20 you're looking at it or whatever, attach some significance to 21 that. Because we have different roles. And, also, some of 22 this stuff I've seen outside the courtroom prior to it being 23 discussed. So I don't want you-all -- didn't I mention to you 24 on the first day that you-all will have your feelers out and 25 pick up absolutely every clue about what's the right thing to 86 1 do? And one of the things I don't want you to do is to read 2 some significance into whether I'm working on my cold or 3 watching the television. Okay? 4 All right. Go ahead, Mr. McGoldrick. 5 MR. McGOLDICK: Judge, with all that, we've 6 tilted it a little just in case you happen to view it. 7 JUDGE POTTER: Okay. 8 Q. Doctor Fuller, we don't have any sound of 9 narration on this, so I'd like if you would come over here 10 and, as the videotape runs, with your pointer explain to the 11 jury what's happening kind of generally. Now, I'm not sure, 12 Doctor, which is the better side for you to be on for vision 13 for the folks. 14 JUROR FITCH: It's so she can hear. 15 Q. Oh, you wouldn't be able to hear? So maybe if 16 you're on this side, but just try not to cut the folks' vision 17 off, and with that I guess we can roll the videotape. And, 18 Mr. Myers, feel free to stop it anytime you want to. 19 Excuse me. If I may, Your Honor, if for any 20 reason you want the videotape stopped, and you may not, I need 21 to tell -- oh, it's actually working? Go ahead. 22 A. What you're going to see is sort of how this 23 process of neurotransmission works. The point here is that 24 there are many different neurons on the brain, as I said, and 25 they are collected together in very complicated ways and they 87 1 are sending messages back and forth all the time. That's 2 fundamentally how the brain works, and you're going to see 3 some of these individual neurons depicted in terms of how they 4 are releasing transmitters and those transmitters -- I told 5 you that the neurons are very close together. This is more 6 how they would look. The space between them is very, very 7 tiny. And in order to see what is going on in there, they're 8 being pulled apart so that you can actually see those 9 transmitter molecules as they are acting, and this space in 10 between them is called the synaptic cleft. This is a synapse, 11 and this space is the synaptic cleft, the synaptic gap. So 12 these nerves here are sending messages to these nerves here 13 and they do it again by releasing particular chemical 14 substances called neurotransmitters, and this is one 15 neurotransmitter, it's released out of this neuron. 16 This one is depicted as a little blue square, 17 and it is combining with a receptor which recognizes that 18 particular neurotransmitter. That's what a receptor is for is 19 to let this neuron know that I've received a message, do 20 whatever you're supposed to do in response to that blue cube, 21 which might be norepinephrine or something else. So this is 22 the neuron that's receiving the signal and that's how the 23 signals are sent throughout our brains. That's how I know 24 what nerves to use, what thoughts to think, that's how you 25 understand what's being said. 88 1 The transmitter, after completing the signaling 2 of this neuron again can be activated one way by this process 3 of reuptake. So this pump you actually now see going and 4 whenever a molecule of that particular neurotransmitter 5 combines with that pump, it is taken into this neuron. This 6 could be called a transporter or a pump. Again, those are 7 specific. A transporter will be there for the purpose of 8 transporting one particular transmitter and will ignore others 9 that might come into contact with it. 10 Now, there are many different neurotransmitters 11 in the brain. I've mentioned some. The ones I mentioned are 12 what we call monoamines; norepinephrine, dopamine and 13 serotonin, but there are other kinds, as well, neuropeptides 14 and many others. This is just to emphasize the point that 15 each transmitter is different and you see three different 16 symbols here to represent three different transmitters. 17 Each transmitter acts specifically on a receptor 18 for that particular neurotransmitter and it causes to happen 19 in this target neuron whatever that neuron has been 20 preprogrammed to do. Sometimes the neuron will fire faster; 21 sometimes it will fire slower; sometimes it responds 22 differently to something else when it's activated by its 23 transmitter. But those transformers, whether or not they're 24 in the synaptic cleft, they cannot only touch these neurons, 25 but they can touch those neurons, as well. 89 1 This is now going to show you how fluoxetine 2 affects serotonin neurons and serotonin neurotransmission. 3 This is a moving version of what I explained on those charts. 4 A serotonin molecule is released. This serotonin nerve is 5 sending a signal to this one, the serotonin acts on this 6 postsynaptic neuron. This is called a presynaptic neuron; it 7 causes something to happen. Now, the serotonin has been made 8 within this neuron through a chemical process from tryptophan, 9 the amino acid that I mentioned. It's stored in these storage 10 granules or vesicles, and then when the nerve says "I want to 11 send a signal to this nerve," then it releases a molecule of 12 serotonin which comes out into the synaptic cleft. It 13 combines with this receptor site to trigger this response, the 14 appropriate response in this neuron. Again, these receptors 15 are specific and they cause something to happen when serotonin 16 comes into contact with them, but not if some other 17 neurotransmitter contacted them. 18 And the serotonin now you see in the synaptic 19 cleft coming in contact with this transporter and it is taken 20 back inside. It's already inactive now, it can't act on these 21 receptors while it's in there, and it can either get reused in 22 the storage granule again or it can be destroyed 23 enzymatically. So this process is specific for serotonin. 24 The uptake carrier on a serotonin neuron will take up only 25 serotonin. 90 1 The enzyme that I mentioned is called monoamine 2 oxidase. That is what destroys the serotonin. It also 3 destroys other monoamines. Now, I mentioned evidence that 4 depression as an illness may be caused by too little 5 serotonin, not enough serotonin being released into these 6 synaptic clefts. This represents now a molecule of fluoxetine 7 that combines with this transporter. And when it combines 8 with that transporter, it essentially stops it and keeps it 9 from being able to take up serotonin, so that when this uptake 10 carrier is stopped, whenever a molecule of serotonin is 11 released out into the synaptic cleft, it can still act on 12 these receptors, but it can't be inactivated by being taken 13 back up and so it stays out here in the synaptic cleft. 14 What you're going to see here is the molecule of 15 serotonin coming into contact with the transporter but it's 16 not working, it's not taking it back up, so it stays here in 17 the synaptic cleft. As more molecules of serotonin are 18 released, then the concentration of serotonin here in the 19 synaptic cleft is increased. And I mentioned the 20 extracellular serotonin can be measured by this technique of 21 microdialysis, so we can actually see these increases in 22 extracellular serotonin after fluoxetine treatment in 23 laboratory animals. So there is an increase in the 24 transmission of serotonin signals as a result of blocking this 25 uptake carrier. And whatever molecular changes are taking 91 1 place in this postsynaptic target neuron, they are now taking 2 place at a faster rate than they had been before the uptake 3 carrier was inhibited. You have amplified or magnified these 4 serotonin signals. 5 Now, I was talking earlier about the fact that 6 as serotonin accumulates here in the synaptic cleft, it not 7 only comes in contact with these receptors that are located 8 over here on this postsynaptic neuron, but in addition to 9 these receptors on the target neuron there are also receptors 10 that are located here on the serotonin neuron itself. So that 11 the serotonin molecules can come into contact not only with 12 these postsynaptic receptors but also with this autoreceptor, 13 the serotonin neuron. And when that happens the serotonin 14 neuron says, "Okay. There's an increased amount of serotonin 15 out here. I'm not going to release as much serotonin as I've 16 been releasing." And so the firing of those serotonin neurons 17 is reduced and the rate at which they release serotonin is 18 reduced, so that the increase in the extracellular serotonin 19 is only up to a limited extent, not any further. 20 And whenever there are other sets of neurons 21 around, like norepinephrine neurons or dopamine neurons or 22 something else, fluoxetine is only blocking the uptake of 23 serotonin. It doesn't affect uptake processes that are going 24 on in other neurons. The tricyclic antidepressants drugs, on 25 the other hand, not only block serotonin uptake, but they also 92 1 block the uptake of norepinephrine and possibly other 2 neurotransmitters like dopamine. And in addition to their 3 blocking the uptake, they also have another set of actions, 4 they act on these receptors that I talked about: cholinergic 5 receptors, the histaminic receptors, the alpha adrenergic 6 receptor, and those actions are thought to be responsible for 7 the prevalent side effects of the tricyclic drugs. 8 So by having a specificity in its action, one of 9 the major advantages of Prozac is not that it acts in a higher 10 percentage of patients, but that it acts with much fewer side 11 effects so that some patients who couldn't take the tricyclic 12 drugs are able to take Prozac. 13 And that, in essence, is a simplified view of 14 how neurotransmission works in the brain and how Prozac 15 influences that by magnifying serotonin signals. 16 Q. Doctor Fuller, thank you very much. I think you 17 can resume the stand now. 18 And, Your Honor, it will take us 20 seconds to 19 just move this out of the way. 20 Doctor, having spent the time we took to try to 21 explain the serotonin system and Prozac and how it works at a 22 scientist's level, let's turn back the clock a little, and I 23 want to ask you to tell the jury about how this medicine came 24 to be and your role in it. You came to Lilly in 1963, I think 25 you told us? 93 1 A. That's correct. 2 Q. Now, can you explain to the jury how the actual 3 discovery of this medicine happened at Eli Lilly, how did it 4 happen, what occurred and who was involved? 5 A. Well, Doctor Brian Molloy, who is a medicinal 6 chemist at Lilly, in 1972 began synthesizing some chemical 7 analogs of a drug called diphenhydramine, which actually is an 8 antihistaminic drug. And the reason he was interested in that 9 particular chemical molecule is that Professor Arvid Carlson 10 in Sweden had reported a year or so before that certain 11 antihistaminic drugs, including diphenhydramine, shared some 12 actions in common with antidepressant drugs. They could be 13 inhibitors of this uptake of monoamines. And Doctor Molloy's 14 intent was to take the diphenhydramine molecule and make some 15 chemically related substances with the idea of getting rid of 16 the antihistaminic activity but maximizing the 17 antidepressant-like activity. 18 He worked with a behavioral pharmacologist name 19 Bob Rathbun -- Doctor Bob Rathbun, who has since retired from 20 Lilly. Doctor Rathbun was testing the chemical compounds, the 21 new chemicals that Doctor Molloy was synthesizing in a simple 22 animal test screen. He was giving mice a drug called 23 apomorphine which lowers the body temperature of those mice. 24 And they knew that antidepressant drugs, that tricyclic drugs 25 would actually counteract that body temperature lowering 94 1 effect of apomorphine. 2 So Doctor Rathbun was testing the new chemicals 3 that Doctor Molloy synthesized for their ability to block the 4 body temperature lowering by apomorphine, and he found in fact 5 that several of the compounds that Doctor Molloy had made were 6 active in that mouse test. That suggested that they did have 7 some antidepressant-like properties that needed to be 8 characterized further. Now, independently of that research -- 9 Q. Excuse me. If I could just interrupt for one 10 second and let you finish after this. So the first part of it 11 is Doctor Molloy is working -- he's a chemist? 12 A. Yes, sir. 13 Q. And he's working trying to invent new molecules? 14 A. That's right. 15 Q. And Doctor Rathbun was taking the molecules that 16 Doctor Molloy was inventing and testing them to see -- in this 17 test you talked about, test to see if they had effects on this 18 system? 19 A. Yes, sir. 20 Q. So that work's going on and in fact they do find 21 some molecules, a variety that do this? 22 A. That's correct. 23 Q. And then what happens next? You were about to 24 say when I interrupted you. 25 A. Doctor David Wong, a biochemist, was 95 1 independently doing some biochemical studies involving rat 2 brain synaptosomes. Synaptosomes are small pieces of nerves. 3 If you think back to those diagrams, I showed you a serotonin 4 nerve terminal. If you take brain tissue and actually grind 5 it up, these nerves pinch off and the endings of those nerves 6 pinch off into little sacs, which would just be the left-hand 7 part here basically, and those are still active in taking up 8 serotonin. So you can actually study that process of 9 serotonin uptake in the test tube using radioactive serotonin 10 and measuring how rapidly it is taken up by these 11 synaptosomes. 12 Doctor Wong was studying the uptake of 13 serotonin, norepinephrine and dopamine, three different 14 monoamines. Doctor Irwin Slater, who was the director of 15 pharmacology in the Lilly Research Laboratories at that time, 16 knew about the work that Doctors Molloy and Rathbun were 17 doing, about these new chemicals that Doctor Molloy had 18 synthesized, and he suggested to Doctor Wong that some of 19 those compounds probably were uptake inhibitors and that he 20 ought to look at them in this synaptosomal test. So Doctor 21 Wong began to do that, and he found that they were in fact 22 uptake inhibitors. These new chemicals were active in 23 blocking the uptake of those neurotransmitters. 24 But what he found was something quite 25 interesting; that some of those new chemicals were fairly 96 1 nonspecific. They blocked the uptake of norepinephrine, 2 serotonin and dopamine. But others of them were very specific 3 or selective in their action. And, in particular, there was 4 one compound which blocked the uptake of serotonin but not the 5 uptake of norepinephrine or dopamine. That particular 6 compound, as a matter of fact, had not been active in Doctor 7 Rathbun's test, but in blocking serotonin uptake in 8 synaptosomes in the test tube it was very effective. And that 9 then became a compound that we were immediately interested in 10 because of the selectivity of its action, and that is the 11 compound that we now call Prozac. 12 Q. Now, you say that all pretty quickly. Did that 13 take a period of time? 14 A. All that happened during the year 1972. It 15 happened -- what I've told you up to now happened within a few 16 short months during 1972. 17 Q. Doctor Molloy is inventing these chemicals. 18 Doctor Wong by these ingenious methods is finding some effects 19 they have, and one of them turns out to have this selective 20 serotonin inhibitor effect? 21 A. Yes, sir. That's right. 22 Q. At the time, it wasn't called Prozac? 23 A. No. 24 Q. What was it called around the laboratory? 25 A. Well, it has a chemical name, of course, but the 97 1 chemical name is very long and complicated, so all of our new 2 chemicals are assigned a serial number for convenience. And 3 the serial number on this particular compound was 110140. 4 Q. You remember that number? 5 A. I wrote that number down a lot of times and 6 that's how we generally referred to it. 7 Q. And this was -- this is a new invention, this 8 compound? 9 A. Yes, sir. It was a new chemical compound that 10 had not existed before Doctor Molloy synthesized it. 11 Q. And after Doctor Wong found what he found, was 12 it viewed at that point that there was potential for it being 13 a useful medicine or not? 14 A. There was certainly a lot of interest in it 15 immediately. 16 Q. Was it at that point a pretty big discovery or 17 not? 18 A. Well, it was an interesting discovery but, 19 again, what happens in the test tube is not enough. You have 20 to have drugs that are effective in living animals. 21 Q. So what happened next and what did you do? 22 A. As I mentioned, I had been interested in 23 studying brain serotonin and had been active in studying brain 24 serotonin for all the time that I had been there, so we had 25 experimental methods that we could apply to the study of this 98 1 new agent to find out does it actually inhibit serotonin 2 uptake in the brain of animals and does it do so selectively. 3 So we did those experiments. We did several kinds of 4 experiments to show that this compound did inhibit serotonin 5 uptake in the brain, not just in the test tube, and that it 6 did that selectively. It didn't block norepinephrine uptake 7 or dopamine uptake in animals and that it didn't have any 8 other action, so far as we could tell, except the blocking of 9 serotonin uptake, and that it did this when it was given 10 orally to rats and mice. It had an adequate duration of 11 action that would make it of interest as a potential drug. 12 And it was at that point that we became 13 convinced that this -- now, for the first time, we had a 14 selective inhibitor of serotonin uptake and in human diseases, 15 in which serotonin was thought to be important, such as 16 depression, this might be a useful medicinal agent. 17 Q. So at this point you thought you might have 18 something that would be useful to help human suffering? 19 A. Yes, sir. 20 MR. SMITH: Objection. Leading, Your Honor. 21 JUDGE POTTER: Sustained. 22 Q. All right. Well, Doctor Fuller, when you did 23 the studies you did, did you also do studies with respect to 24 method of administration? 25 A. Yes, we did. We gave the drug -- typically, we 99 1 give the drug by injection because that's a convenient way of 2 administering drugs to animals. But that is not the route 3 that one ordinarily uses in human beings, so we also gave the 4 drug orally to be sure it would be effective orally. 5 Q. And what were the results of that? 6 A. The results were that it was as effective orally 7 as it was by injection. 8 Q. And did you do work at this point with respect 9 to the duration of the effect of the medicine? 10 A. Yes, we did. 11 Q. Why do you do that? 12 A. Well, again, it's important if a drug is going 13 to be used as a medicine in humans that it have an adequate 14 duration of action. You wouldn't be interested in a compound 15 that had to be given every 15 minutes or so. 16 Q. And what would your conclusions of that be? 17 A. The conclusions were that in rats and mice, 18 which we studied initially and other species later, that it 19 did have a long duration of action. 20 Q. At this point, were -- what were the 21 implications of what had happened to that point? What was to 22 happen next? 23 A. Well, we were excited about having such a 24 compound for the first time and we were interested in 25 developing it, particularly as a drug candidate for the 100 1 treatment of mental depression, and so we characterized it 2 much more completely from a pharmacology point of view; that 3 is, a lot of other people now began to do experiments with 4 this compound to find out does it do anything else that we 5 would not want it to do, does it have any kind of effects that 6 would interfere with it being considered as a candidate for 7 drug development. And those experiments again were done 8 during late 1972 and early 1973. 9 Q. Okay. Without going into all the detail on 10 that, Doctor, one of the kinds of studies you do is so-called 11 pharmacology studies; is that right? 12 A. Yes, sir. 13 Q. And when any organism, an animal or human being 14 takes something in, whether it's orange juice or Prozac or 15 whatever, the body acts on it; is that right? 16 A. That is correct. 17 Q. And what does the body do? 18 A. Well, typically, the body would metabolize the 19 compound to something else, then those metabolites would be 20 excreted into the urine, for example. 21 Q. So whatever we take in typically gets broken 22 down in some way over time by the body? 23 A. Yes, sir. 24 Q. And we have a series of different things it gets 25 broken down into? 101 1 A. Yes, sir. 2 Q. They can break down into one thing and that gets 3 broken down into two others and they get broken down, that 4 sort of thing? 5 A. Yes, sir. 6 Q. And the study of that whole breakdown process is 7 called what? 8 A. We could call that drug metabolism, usually. 9 Q. And those studies have to be done? 10 A. Yes, sir. 11 Q. Certainly before you think of it as being a 12 medicine you have to know those things? 13 A. That's correct. 14 Q. And the FDA requires you to do those things? 15 A. That's correct. 16 MR. SMITH: Your Honor, we'd object to the 17 continuing leading nature of the questions. 18 JUDGE POTTER: Well, it's more or less 19 preliminary. 20 Q. Going back a minute, the results that you had in 21 all your studies and the work you were talking about, were 22 these eventually published? 23 A. Yes, they were. 24 Q. So they were available to the world scientific 25 community? 102 1 A. Yes, they were. 2 Q. Were they published in peer-reviewed journals? 3 A. Yes, sir. 4 Q. Now, when you go into the next phase, you said 5 you're looking for metabolism. What else? 6 A. Well, actually early in 1973, we collectively 7 decided that this compound should be advanced toward clinical 8 trials. And we formally appointed a project team to do that, 9 a group of people whose job it was to coordinate the 10 additional studies that were necessary to show that the 11 compound was safe and appropriate to test in human beings. 12 Q. All right. Well, I think there's an exhibit 13 which has been used earlier in this trial and I'm not going to 14 go over it at length, but maybe you could just sort of orient 15 us to where in this process we are. This is 171, and I think 16 the jury may remember seeing this before. At the point you're 17 talking about where we're starting to test this in animals, 18 where are we on this chart? 19 A. Well, I told you about the original chemical 20 synthesis in the chemical lab there, and then I've told you 21 about the initial animal pharmacology studies that led us to 22 realize that this compound had properties that made it of 23 interest as an antidepressant drug candidate. 24 Q. Kind of in here? 25 A. In that area. And then once the decision was 103 1 made to form the project team, we already knew something about 2 the safety of the compound, but now formal toxicology studies 3 were initiated to obtain enough evidence that the compound 4 would be safe to try on a limited basis in human subjects, and 5 that began in 1973. 6 Q. Why do you do this kind of toxicology testing? 7 A. Well, that's always done to again be sure that 8 the compound is safe; that there would not be any adverse 9 effects that would be associated with the doses that you're 10 going to use and to be aware of what potential toxic effects 11 the drug would cause at any dose. 12 Q. And you also learn something about metabolism 13 and other stuff in there? 14 A. Yes. That is studied during the toxicology 15 studies and also independently of them. 16 Q. You want to do all of this before you do the 17 first human volunteers? 18 A. That's correct. 19 Q. Is it also required by the FDA that you do that? 20 A. Yes, it is required. Before human studies be 21 undertaken, it's necessary to file what is called on that 22 chart an IND, an Investigational New Drug application, and 23 that must contain evidence that there is a basis for studying 24 that compound in humans; that is, the evidence that the 25 compound is a serotonin uptake inhibitor, it increases 104 1 serotonin function, that it therefore would have potential as 2 an antidepressant drug. Those are the reasons we would want 3 to study the compound in humans. And the other part of that 4 is the evidence that the compound is safe to be studied in 5 humans, and that evidence comes primarily from those 6 toxicology studies. 7 Q. So all of these studies -- all of this work gets 8 put into the IND filing and goes to the FDA? 9 A. That's correct. 10 Q. And before you could start on any giving it to 11 humans, the FDA has to look at all that and approve that? 12 A. That's correct. 13 Q. Now, I'm not going to spend much time with you 14 on this, Doctor, but just so you can orient us to the whole 15 flow of it, we then have this yellow block of studies -- 16 phases leading up to NDA approval; is that right? 17 A. Yes, sir. 18 Q. What is the yellow block? What is done in that 19 whole block? 20 A. Well, those are the clinical studies, the 21 studies in human beings. What is shown there is Phase 1, 22 clinical studies would be studies done in normal volunteers. 23 These would not be sick people, these would not be depressed 24 patients in this case; they would be volunteers who take the 25 drug for the first time. It allows you to see are there any 105 1 adverse effects in those patients. It allows you to study the 2 metabolism of the drug, to measure blood levels of the drug, 3 to be sure it is absorbed after oral administration to find 4 out how long it persists in the blood and things of that sort. 5 In fact, in the case of fluoxetine, or Prozac as it later was 6 called, there was an additional information that was obtained 7 in those Phase 1 studies. It turns out that -- I didn't 8 mention this before, but there are serotonin transporters not 9 only on brain neurons but also on blood platelets, so clearly 10 it isn't possible to study in the human what is happening 11 inside the brain, but it is possible to take blood samples and 12 to study what happens in blood platelets. And so it was 13 actually possible to show that fluoxetine at the doses we were 14 giving to these patients was effective in blocking the 15 serotonin uptake carrier on blood platelets. So that told us 16 that the doses that we were giving were effective in blocking 17 serotonin uptake. 18 Q. All right. And, Doctor, so then you move into 19 Phase 2 and 3 where you study it in depressed patients? 20 A. That's correct. 21 Q. And you study it for efficacy; does it work? 22 A. That's correct. 23 Q. And safety, whatever its side effects? 24 A. Yes, sir. 25 Q. All right. Now, at the end of this phase, the 106 1 preclinical pre-human-being animal phase, did it still look 2 like you had a promising medicine as it did after you and 3 Molloy and Wong and others had done their work? 4 A. Yes, sir. 5 Q. All right. Let me put this back, if I may. 6 When you do the toxicological testing on animals 7 that you talked about, Doctor Fuller, what are you really 8 trying to do? 9 A. Well, you are trying to find out what are the 10 toxic effects that this compound is capable of producing and 11 at what doses does it produce those effects. 12 Q. Is it true, Doctor, that if you take many kinds 13 of things, even table salt, too much can cause toxic effects? 14 A. That's exactly right. 15 Q. Are there any substances where that doesn't 16 happen? 17 A. I don't know of any. 18 Q. Even water, I suppose? 19 A. Certainly water. 20 Q. So you give the animals high doses to see at 21 real high doses what kind of effects you might have? 22 A. That's correct. 23 MR. SMITH: Objection. Leading, Your Honor. 24 JUDGE POTTER: Overruled. Go ahead. 25 Q. And is that kind of testing required? 107 1 A. It is, yes. It is required before compounds are 2 given to humans that studies of that sort be done to verify 3 that they are safe. 4 Q. How high are the doses you might give to 5 animals? Are they real high? 6 A. The doses generally would be high enough to 7 actually be lethal to the animals, and then other doses that 8 were nonlethal but still producing toxic effects would be 9 studied in more detail. 10 Q. Do you have to do this to make sure they're 11 safe? 12 A. Yes, sir. And to know at what doses it would 13 not be safe. 14 Q. And this is required by the federal government? 15 A. It is required by the federal government. It 16 clearly is something that would be done by any prudent 17 investigator who wanted to study a drug in humans. 18 Q. It's good medicine, as well? 19 A. Yes, sir. 20 Q. How extensive was the animal testing? 21 A. The toxicology studies with Prozac began in 22 1973, but continued over a long period of time after that. 23 The very initial studies that were done and concluded and 24 reported in the Investigational New Drug Application involved 25 study of the compound in several species of animals and 108 1 administration of the compound by different routes, 2 particularly orally, because that was the intended route of 3 use in humans. I think there were 90-day toxicology studies 4 done in rats and dogs and other kinds of more acute toxicology 5 studies done in other species. 6 Q. About how long did that take? 7 A. It took probably a few years for the completion 8 of all the studies -- all of the toxicology studies that went 9 into that Investigational New Drug Application and then, as I 10 said, they continued beyond that, as well. 11 Q. Did any other independent party ever look at 12 Lilly's testing in the animal phase to see if it was 13 appropriate? 14 A. Yes. I think there were consultants that 15 examined the data that were being generated. Actually, the 16 initial toxicology studies were reviewed with the Food and 17 Drug Administration before the Investigational New Drug 18 Application was actually formally submitted. 19 Q. So the FDA took a look at all these things? 20 A. Yes, sir. 21 Q. Were many of these studies published in the 22 scientific literature? 23 A. The pharmacology studies were certainly all 24 published; I don't think all the toxicology studies were 25 published. It's common that those are not published with 109 1 drugs because they are not particularly -- they're not 2 necessarily of importance scientifically. Again, any drug can 3 produce toxic effect at a high enough dose, and one doesn't 4 always publish the studies like that. 5 Q. Now, you didn't actually do any of the testing 6 or supervise any of the testing of human beings? 7 A. No, I did not. 8 Q. Medical doctors did that and others? 9 A. That's correct. 10 Q. My question to you at this point is are you 11 generally familiar, however, with the process? 12 A. Yes, I am. 13 Q. And you became aware of what the studies showed 14 in human beings? 15 A. Well, I was chairman of this project team that 16 was responsible for coordinating these various studies, so I 17 was aware when the clinical studies were beginning and I would 18 hear reports of those studies as they progressed. 19 Q. Now, some of the studies with -- on first trying 20 it on people to see if it would work and how it would work -- 21 could I have the time line, John? Thank you, John -- are what 22 we call open label. What's that mean? 23 A. Well, those are studies that are not done in a 24 double-blind fashion. A double-blind study would be a study 25 in which neither the patient nor the physician is aware of 110 1 what the individual patient is receiving. Some patients would 2 be receiving the drug, some patients would be receiving a 3 placebo, that is, the same capsule but not containing any 4 drug. And in a double-blind study, the patient would not know 5 if he or she was receiving an active medication or a placebo 6 and the clinical investigator would not know that, either; 7 this would be called a double-blind study. 8 The initial studies in the testing of new 9 compounds are commonly not done in that double-blinded way, 10 but they are so called open-label studies. The physician 11 knows that the patient is receiving a drug, and the idea is to 12 begin to explore is there any effect of this drug and at what 13 doses do we begin to see any effects of this kind. 14 Q. So in the beginning you're more apt to have the 15 open label? 16 A. That's correct. 17 Q. And then as you go on, you move into the 18 controlled studies? 19 A. As you begin to get some indication of what dose 20 would be appropriate to try, then you would set up a 21 double-blind study to be absolutely certain is there an effect 22 of this medication or not. 23 Q. Doctor, you can have a controlled study that 24 isn't blinded? 25 A. That's certainly correct. 111 1 Q. And in that, what do you do, what are you 2 comparing? 3 A. Well, I think you could mean different things by 4 having a controlled study, but typically one control would be 5 to give a placebo, to give something which shouldn't produce 6 any effect. So if the patient got better while taking 7 placebo, you would know that the improvement had nothing to do 8 with a drug but to something else. You might also include in 9 a controlled study what we would call a positive control, 10 include a drug which has already been shown to be effective in 11 that condition, to be sure that the methods you were using 12 were capable of detecting a drug that really did work. 13 Q. So you can have a controlled study that isn't 14 blinded? 15 A. Yes, sir. 16 Q. And then there's something -- the next step is 17 something that's single-blinded, is it? 18 A. That term is sometimes used, yes. 19 Q. What does that mean? 20 A. Well, that would mean, for example, that the 21 investigator might know what the patient was getting, but the 22 patient wouldn't know. 23 Q. The investigator is the doctor who's 24 administering the medicine? 25 A. Yes, who's supervising and doing the study. 112 1 Q. The doctor may know what the patient is taking, 2 but the patient wouldn't? 3 A. Yes. 4 Q. Why the blinding? Why is that important? 5 A. Well, it's important in any kind of medical 6 study, but it's probably of particular importance with 7 diseases like depression, which sometimes are cyclic 8 illnesses. Sometimes a patient will get better even without 9 any kind of treatment. Sometimes a patient will get better on 10 placebo simply because the patient has entered a study, is 11 expecting to get better; factors like that can often influence 12 the outcome of a clinical setting, especially in some disease 13 like depression. So it's important to have double-blinded 14 controlled studies to be absolutely certain about your 15 decision is this drug effective or not effective. 16 Q. So at least the purpose of the single blind is 17 that the patient doesn't know what he or she is getting, so it 18 won't affect in any way that patient's symptoms or how they 19 feel or how they think they feel? 20 A. That's correct. 21 Q. They don't know whether they're getting medicine 22 or not? 23 A. That's correct. 24 Q. And the next step is double-blind and that's 25 again what? 113 1 A. Again, neither the investigator nor the patient 2 would know what an individual patient was getting. They would 3 both be aware that some patients would be receiving the test 4 drug, some patients would be receiving placebo, and if there's 5 a positive control, some patients would be getting the 6 positive control but they would not know what an individual 7 patient is receiving. 8 Q. And is there something called triple blind? Did 9 you ever hear of that? 10 A. Triple blind. There probably is. I'm not sure 11 I know what would be meant by that at the moment. 12 Q. Is that something if it happened, it happened 13 later in the phase? 14 A. Probably so. 15 Q. All right. So in these phases of testing of 16 humans you have open label, unblinded, then you have blinded 17 studies. Do you -- do you have a general familiarity with how 18 extensive this testing was, the clinical testing compared to 19 other medicines? 20 A. Well, I have some general feel of numbers of 21 patients who were included in the various phases. Certainly 22 as the medication moved along, there were increasing numbers 23 of patients and, you know, by the end, there certainly were 24 hundreds of patients that had been treated for different 25 periods of time and it was certainly for an antidepressant 114 1 drug, which needs to be given chronically, the testing was far 2 more extensive with this drug than it would be for something 3 like an antibiotic which is only going to be used for a short 4 period of time. 5 Q. Doctor, after all of that testing was done, did 6 Eli Lilly believe that it had a safe and effective medicine? 7 A. Yes, sir. 8 Q. Do you, knowing all you know, of all the work 9 you've done, believe that it was safe and effective for 10 treatment of depression? 11 A. Well, I think there was no doubt at the time we 12 submitted the New Drug Application, but certainly the 13 extensive use of the drug since then has verified that it is 14 safe and effective. 15 Q. All right. Now, did there come a time, there 16 did, when the FDA approved it as a safe and effective 17 medicine? 18 A. There did come that time. 19 Q. And that was approximately when? 20 A. That was approximately the last week of December 21 1987. 22 Q. All right. Let's come back for a minute to 23 something you mentioned earlier. You said at some point that 24 you and others received something called the Discoverers 25 Award? 115 1 A. Yes, sir. 2 Q. First of all, who received it? 3 A. Doctor Brian Molloy, Doctor David Wong and 4 myself. 5 Q. Could you explain to the jury what that award 6 is? 7 A. Well, it's an award which is given by the 8 Pharmaceutical Manufacturers Association. It's given every 9 year. I think it's been given for about the last eight years 10 or so. And it is given in recognition of the discovery of a 11 drug which they consider to be particularly significant, and 12 it's given to individuals who were involved in the initial 13 discovery of that drug, not to recognize things that happened 14 later, because there are many, many people involved in the 15 development of a drug at various stages along the way. But 16 the three people in this case that were judged by the PMA, 17 Pharmaceutical Manufacturers Association, to have been 18 responsible for the initial discovery of the drug were Doctors 19 Wong and Molloy and myself. 20 Q. And did you get that award at a meeting of some 21 sort? 22 A. It was presented at the -- in Washington D.C., 23 in one of the Senate office buildings. 24 Q. Are there other medicines where the discoverers 25 and inventors have received this award? 116 1 A. There have been I think about eight. 2 Q. Do you know any of them? 3 MR. SMITH: That would be immaterial, Your 4 Honor. 5 JUDGE POTTER: Overruled. 6 A. They include a number of investigators, I think 7 a few of whom have gone on to win Nobel prizes, as a matter of 8 fact, Sir James Black being one of those. 9 Q. Is this kind of like an Academy Award for 10 neuroscience, or is that not true? 11 A. It's I suppose approximately like that. There 12 were not nearly as many people at the ceremony as we see at 13 Academy Award presentations, but the award itself is a trophy 14 of the sort that you would get. 15 Q. It looks like a molecule? 16 A. No. It's actually sort of like the Washington 17 Monument. It is a crystal obelisk. 18 MR. McGOLDRICK: If the Court, please, I am 19 about to go into a reasonably long session. 20 JUDGE POTTER: We'll go ahead and take the lunch 21 recess at this time. As I mentioned to you-all before, can 22 you -- well, first of all, can you break your habit enough to 23 get back at, what, quarter of two? Is that okay? Does that 24 give you your hour and a half? 25 As I mentioned to you-all before, do not permit 117 1 anybody to speak to or communicate with you about any topic 2 connected with this trial, and any attempt to do so should be 3 reported to me. Do not discuss it among yourselves or form or 4 express opinions about it until it is finally submitted. 5 We'll stand in recess till 1:45. 6 (LUNCH RECESS) 7 SHERIFF CECIL: The jury is now entering. All 8 jurors are present. Court is back in session. 9 JUDGE POTTER: Please be seated. 10 Doctor, I'll remind you you're still under oath. 11 Mr. McGoldrick. 12 MR. McGOLDRICK: Thank you, Your Honor. 13 Doctor Fuller, good afternoon. 14 A. Afternoon. 15 Q. Now, Doctor Fuller, when Doctor Breggin was here 16 testifying for the Plaintiff did you have occasion to read his 17 testimony or part of it? 18 A. Yes, I did. 19 Q. He said a number of things in his time in this 20 courtroom, and I'd like to ask you about some of them and 21 whether they're right or wrong. First, Doctor Breggin said 22 that Prozac can shut down the nerve so that it stops producing 23 serotonin. Is that correct? 24 A. No. That is not correct. 25 Q. Why not? 118 1 A. Well, what happens as a result of the increase 2 in extracellular serotonin following uptake inhibition by 3 fluoxetine, or Prozac, is that the autoreceptors on the 4 serotonin neurons sense that increased amount of serotonin and 5 they begin to make less serotonin, but they certainly are 6 still making serotonin and they are still firing and releasing 7 that serotonin. 8 Q. Are they in any sense shut down? 9 A. They are not shut down in the sense I would 10 understand that word; they simply are releasing serotonin at a 11 slower rate than they were before. 12 Q. Is serotonergic neurotransmission, while you're 13 taking Prozac, increased? 14 A. It is increased, again for the same reason, that 15 there is an increased amount of extracellular serotonin. 16 Q. All right. Doctor Breggin has said that Prozac 17 overarouses or jacks up the serotonin system, producing a 18 stimulant profile. Is that correct? 19 A. That is not correct. 20 Q. Why not? 21 A. Well, fluoxetine doesn't cause a stimulant 22 profile. The pharmacologic actions of fluoxetine are very 23 different from those of stimulant drugs such as amphetamine. 24 I'm not certain what Doctor Breggin might have meant by that 25 term "jacked up." I don't think neuropharmacologists use that 119 1 word, and I frankly am not sure what he might have meant by 2 that, or even the term, what, hyperarouse? 3 Q. Overarouse. 4 A. Overarouse. I honestly don't know what he might 5 have meant by that. But what fluoxetine does is to increase 6 serotonin transmission. What stimulant kinds of drugs do is 7 principally to act by catecholamine mechanisms. They affect 8 dopamine neurons in particular and also norephinephrine 9 neurons, so the mechanism of action is not at all like that of 10 a stimulant drug. 11 Q. Doctor Breggin has said that Prozac produces a 12 profile virtually indistinguishable from the amphetamines. Is 13 that correct? 14 A. Well, that simply is not correct. I have done a 15 lot of research on amphetamines and, in fact, I think I have 16 published more papers on amphetamine than I have on 17 fluoxetine, probably. And I am familiar with what amphetamine 18 does and with the studies of pharmacologic actions of 19 amphetamines, as well as certainly those of fluoxetine, and 20 they simply are quite different drugs. They are chemically 21 different and they are, more importantly, pharmacologically 22 different. The neurotransmitters on which they act are simply 23 different neurotransmitters. 24 Q. Is Prozac, fluoxetine, like an amphetamine or 25 not like an amphetamine? 120 1 A. It is not like an amphetamine. 2 Q. In what ways? 3 A. Well, again, chemically it is not like an 4 amphetamine. The chemical structure of fluoxetine is very 5 different from that of amphetamine. Pharmacologically, 6 amphetamine acts principally by causing the release of a 7 neurotransmitter called dopamine, which fluoxetine does not 8 do. The effects of amphetamine are mostly due to the 9 increased function of dopamine neurons and also increases in 10 norepinephrine neurons. The consequences of that are very 11 different than the consequences of increasing serotonin 12 function. So there essentially is not a pharmacologic 13 similarity between amphetamine and fluoxetine, and certainly 14 no chemical similarity. 15 Q. All right. Let me return to one thing very 16 briefly. 17 Do we have that chart? Thank you. 18 Turning to this chart again, Doctor Fuller, your 19 work primarily and that of Doctors Fuller -- excuse me -- 20 Doctor Molloy and Doctor Wong and others took place in this 21 early part of this time line, in the blue and red area; is 22 that right? 23 A. Well, our initial work took place at that time. 24 I continued to do experiments on fluoxetine. 25 Q. And you've continued to do that to this day? 121 1 A. Yes. 2 Q. But the work in the yellow phase here with 3 clinical trials, that work was done by others, by clinical 4 investigators and others at Lilly who were working with the 5 clinical investigators? 6 A. That's correct. I was not directly involved in 7 those studies. 8 Q. Those are on humans, and whatever effects one 9 might see in those studies someone else will talk about, not 10 you; is that right? 11 A. That's correct. 12 Q. Now, let's turn to another subject, and that is 13 the subject of aggressive or violent behavior. First of all, 14 has it been part of your scientific work over the years to 15 study and know about and be aware of the science on any 16 relationship between serotonin and aggressive behavior, and 17 fluoxetine and serotonin and aggressive behavior? 18 A. Well, yes. It has been part of my 19 responsibilities to be aware of all kinds of functions that 20 serotonin neurons are involved with in the brain. I have done 21 experiments in my own laboratory in collaboration with other 22 scientists on many different kinds of functional effects that 23 serotonin can influence, and that includes to some degree 24 effects on aggressive behavior. I certainly have been aware 25 of the literature of the work that other scientists have done 122 1 on the important relationship between brain serotonin neurons 2 and aggressive behavior. 3 Q. Doctor Fuller, from your studies, your 4 scientific work, your review of the literature, scientific 5 literature and your general knowledge and expertise, do you 6 have an opinion as to whether or not Prozac can cause 7 aggressive or violent behavior? 8 MR. SMITH: May we approach the bench, Your 9 Honor? 10 (BENCH DISCUSSION) 11 MR. SMITH: This was covered last night in the 12 Court's ruling that excluded the -- any evidence concerning -- 13 from this Witness concerning whether or not Prozac causes 14 aggressive behavior in the literature, anything other than 15 animals, by virtue of the Court's ruling last night. 16 MR. McGOLDRICK: If Your Honor please, I'm not 17 now asking about Mr. Wesbecker; I'm not asking about the 18 literature on humans; I'm asking him about his opinion on 19 aggressive and violent behavior. I didn't think that had 20 anything to do with this. 21 JUDGE POTTER: Mr. Smith, I didn't interpret my 22 ruling last night to say that he couldn't express his opinion; 23 I just cut him back on his slides and his reference to outside 24 literature. Objection is overruled. 25 (BENCH DISCUSSION CONCLUDED) 123 1 Q. Doctor Fuller, let me try to ask that again so 2 you can have it in mind. From all of your work, your studies, 3 review of science in general and knowledge and expertise, do 4 you have an opinion for this jury as to whether or not Prozac 5 can cause violent or aggressive behavior? 6 A. Yes, I do. 7 Q. What is that opinion? 8 A. I don't believe it does. 9 Q. And what in a general way, at least, is your 10 basis for saying that? 11 A. Well, that idea would be totally contrary to a 12 large body of experimental evidence that exists showing the 13 importance of serotonin in terms of aggressive behavior. All 14 of the evidence would suggest that drugs which increase 15 serotonin function reduce aggressive behavior, and that has 16 been shown in many kinds of experimental studies. 17 Q. My question actually was, do you have an opinion 18 as to whether it increases aggressive or violent behavior. 19 A. My opinion is that it does not. 20 Q. Do you have an opinion as to whether it makes it 21 stay the same or reduces aggressive and violent behavior? 22 A. There have been a lot of studies showing that it 23 reduces aggressive behavior. 24 Q. All right. Now, back to Doctor Breggin. Doctor 25 Breggin has suggested that Prozac can cause violent-aggressive 124 1 behavior, and he pointed to two examples I'd like to ask you 2 about. In all of the animal testing that was done, he pointed 3 to some cats that hissed and growled, and he pointed to a -- 4 one dog which bit a laboratory technician. Do you remember 5 those instances? 6 A. I'm aware of those incidents, yes. 7 Q. All right. Now, first, let me ask you -- and 8 this may have to be an approximation, but approximately how 9 many animals altogether have been studied in connection with 10 Prozac; would it be hundreds, thousands, tens, what? 11 A. You're referring to animals that received Prozac 12 in studies done anywhere? 13 Q. Well, let's start with that, yeah. 14 A. Well, I couldn't come up with an accurate 15 estimate. When we first began publishing on fluoxetine in 16 1974, we had received large numbers of requests for samples of 17 the drug to be used experimentally by investigators around the 18 world, and we have sent out hundreds, I suppose thousands of 19 such samples. So it has been used in experiments done by 20 people throughout the world in a large number of animal 21 species, and I couldn't begin to estimate what those would 22 total up to, but in terms of number of animals it would be 23 thousands upon thousands. 24 Q. If you can't tell me, don't, but is it true that 25 it would be more than 5,000 or 10,000? 125 1 A. I feel confident it would be more than those 2 numbers, yes. 3 Q. All right. Now, let's talk about the episode 4 with the cats. First of all, to refresh our recollection, 5 what was that episode, if you recall? 6 A. The hissing and growling that was referred to 7 was observed in studies that were being done by Doctor Irwin 8 Slater and his associates, who were studying the effect of 9 fluoxetine on sleep in cats and in rats. 10 Q. And in the particular study we're talking about, 11 how many cats were being studied, if you recall? 12 A. I think he had six cats in that study. 13 Q. And do you recall, did that study reflect how 14 many of those cats hissed and growled? 15 A. I don't believe it mentioned the number in which 16 those particular symptoms were observed, to the best of my 17 recollection. 18 Q. But it did use the word cats, plural? 19 A. Yes, it did. 20 Q. So we can imagine it's at least two? 21 A. That's a safe assumption. 22 Q. Did it appear to be all six or could you tell 23 that? 24 A. My impression is that it was not all the cats, 25 but I would have to look at the paper to be certain if it says 126 1 that. 2 Q. Somewhere in there, above two to six. Now, were 3 there any reasons beside the possible use of Prozac in that 4 study that might have caused that kind of behavior in the 5 cats? 6 A. Well, I didn't participate in the study, of 7 course. I believe someone -- Doctor Slater or someone 8 suggested that the cats had not urinated, and that might have 9 been somehow related to their hissing and growling but I don't 10 know that. 11 Q. In the study, what were they doing with these 12 cats? 13 A. They were actually measuring sleep patterns in 14 the cats by means of monitoring EEG, through electrodes that 15 were implanted in the cats' brains. 16 Q. And what would they do to the cats every day? 17 A. Well, they would treat the cats and they would 18 take them out of their cages to measure, to record from these 19 electrodes. 20 Q. And would that kind of treatment of the cats in 21 any way affect the cats' behavior? 22 A. Well, I think it might. I have not done those 23 kinds of experimental studies myself with cats. In fact, I've 24 not worked very much with cats as a laboratory animal. My own 25 observations about cats, my daughter has three cats and I'm 127 1 around those cats a lot, and my own observations are -- I can 2 make one of the cats, for example, aggressive by trying to pet 3 the cat; I'm not sure why. Some days the cat bites me and 4 some days he purrs. My own observations are that cats' 5 behaviors are characteristically somewhat unpredictable. 6 Q. All right. Let's take the example of the dog, 7 the one dog who bit a laboratory technician. Are you familiar 8 with that episode? 9 A. I remember that being reported. 10 Q. What was being looked at in that study? 11 A. That was a toxicology study in which the toxic 12 effects of fluoxetine at high doses were being examined. 13 Q. And were there any reasons relating to the way 14 that study was being conducted as to why that dog might have 15 been annoyed or irritated? 16 A. Well, he was getting a toxic dose of the drug. 17 Q. What's that mean? What's that doing to the dog? 18 A. I don't remember what the signs of toxicity were 19 that were being observed, but, again, the purpose of the study 20 was to give high doses of the drug sufficient to cause toxic 21 effects. It was a toxicology study. 22 Q. And do you have any sense as to, to your 23 knowledge, as to why the dog might have reacted in the way it 24 did? 25 A. Well, I know, again, from personal rather than 128 1 professional experience that when dogs are in pain or sick 2 they can bite. 3 Q. Any reason why this dog would have been in pain 4 or sick in this study? 5 A. He would have been sick because he was getting a 6 toxic dose of a drug. 7 Q. As you sit here today, can you say exactly why 8 those cats hissed and the dog bit? 9 A. No, I certainly can't. 10 Q. But do you believe that it was related to their 11 using Prozac? 12 A. Well, in the case of the cats, I doubt that it 13 was related to the use of Prozac, simply because that hissing 14 and growling -- it wasn't biting in the cats, I don't believe, 15 it was hissing and growling -- went away while the cats 16 continued to receive Prozac, so it probably wasn't directly 17 related to the drug. It may have been related to the fact 18 that the animals were being taken out of the cage more often 19 than usual or something like that. I simply don't know. I 20 wasn't involved in that study. 21 In the case of the dog, I think it was related 22 probably to the administration of Prozac, because Prozac was 23 being given at a toxic dose and, again, the animal was 24 purposely being harmed by that drug. 25 Q. The animal was in distress because the medicine 129 1 was being given in high doses? 2 A. That's correct. 3 Q. Are these doses typically very high? 4 A. The doses in the toxicology study are, by 5 design, whatever dose it takes to produce toxic effects. A 6 toxicology study has to produce a toxic effect; that's the 7 purpose of the study. 8 Q. And this is the kind of thing the FDA requires? 9 A. Yes, it is. 10 Q. Now, is there any other evidence or reason to 11 believe that Prozac was not the cause for this behavior in 12 these few laboratory animals? 13 A. Well, I think by far the major reason is that 14 those studies were being done for other reasons. These are 15 observations that were written down by people who were 16 observing the animals. And I have no reason to doubt their 17 observations, but the point is -- my point now is that they 18 were not studies being done for the purpose of evaluating the 19 effect of Prozac on aggressive behavior. In fact, there have 20 been a lot of studies of that sort that have been done, and 21 the evidence from those studies is entirely in the opposite 22 direction, that Prozac reduces aggressive behavior. 23 Q. What kinds -- just focus on the type of evidence 24 there exists that Prozac does not cause aggressive behavior or 25 even reduces it. 130 1 A. Well, I think the evidence that it doesn't cause 2 it is simply that it has never been observed in any controlled 3 study done for the purpose of determining the effect on 4 aggressive behavior. Indeed, as I mentioned, those studies 5 have all shown that fluoxetine, or Prozac, reduces aggressive 6 behavior. That is simply part of a larger body of scientific 7 data showing that serotonin is an important neurotransmitter 8 in modulating aggressive behavior. 9 Q. What's modulating mean? 10 A. Affecting, controlling, that sort of thing. And 11 these studies as a whole have shown that increasing serotonin 12 function by whatever means, by means of Prozac or by means of 13 some other kind of drug, causes a decrease in aggressive 14 behavior; and that doing the converse, doing something which 15 decreases serotonin function by giving a drug or making 16 lesions of serotonin nerves in parts of the brain or whatever, 17 those types of modulation of serotonin function always cause 18 an increase in aggressive behavior. So everything that is 19 known about the importance of serotonin and aggressive 20 behavior is exactly contrary to the idea that Prozac would 21 cause aggressive behavior. 22 Q. And so these -- this scientific work has been 23 done with serotonin itself? 24 A. There's different kinds of studies that have 25 been done. There are studies of the sort that I just 131 1 mentioned in which some manipulation is performed on an animal 2 to change serotonin function up or down and see how that would 3 affect aggressive behavior. Again, anything that increases 4 serotonin function decreases aggressive behavior; Prozac or 5 other drugs do that. Anything that decreases serotonin 6 function increases aggressive behavior, the opposite effect. 7 In addition to those kinds of studies, there are 8 other studies that have been done to investigate the influence 9 of serotonin as a brain neurotransmitter on aggressive 10 behavior. For example, serotonin concentration in the brains 11 of animals have been measured, and it has been found that more 12 aggressive animals have less serotonin and vice versa. One of 13 the interesting studies that was done in that regard fairly 14 recently by some Russian investigators used silver foxes, 15 which are bred in Russia for the purpose of making fur coats 16 out of them and fur hats and whatever else they make. 17 MR. SMITH: May we approach, Your Honor? 18 (BENCH DISCUSSION) 19 MR. SMITH: This is an article that was 20 specifically prohibited in the Court's order of last night. 21 This is the silver fox article that came out as one of the 22 ones that they listed in these additional materials. 23 JUDGE POTTER: Mr. McGoldrick? 24 MR. McGOLDRICK: I realize Your Honor's ruling. 25 It seems to me that the scientific work that supports that 132 1 Prozac doesn't cause violence and aggression is part of this 2 man's expertise, it was disclosed early. I'm not asking him 3 now to name the chapter and verse of the article or anything; 4 what I'm saying is that these studies are important. Doctor 5 Breggin was allowed to take us on a tour of the literature. I 6 was here for that. 7 JUDGE POTTER: And I'm assuming that some of 8 your later witnesses are going to do exactly the same thing. 9 MR. McGOLDRICK: Well, but this man, Your Honor, 10 is the man who could tell us. He's the expert in this area; 11 the other witnesses are not. He's the one listed as that. 12 He's the one who can tell us about it, and I believe Mr. Smith 13 was informed about it. 14 MR. SMITH: No, not this article. This article 15 was something that was just disclosed to us yesterday. It was 16 never identified. 17 MR. McGOLDRICK: The entire body of scientific 18 literature was what was fair game for Doctor Breggin. 19 MR. SMITH: And he brought in boxes. 20 JUDGE POTTER: Let's not get into Doctor Breggin 21 because what we're dealing with here is kind of what this guy 22 was presented as. And it's my understanding looking at the 23 pretrial disclosures he was presented as kind of a fact 24 witness that had some opinions about his work and how Prozac 25 worked. And I ruled last night that his relying on all these 133 1 articles and things that just recently came in, I wasn't going 2 to allow him to do it. And I don't know what you had planned 3 for him, but my impression was that except for some sort of 4 broad sweeps for an expert, you don't see anything -- he was 5 going to be kind of cut off because, you know, I haven't gone 6 back and read his deposition, but they showed me some stuff 7 last night that said, you know, that he'd testify about 8 certain things when they examined him and they asked him if he 9 had any other opinions. He said no, he hadn't heard about 10 Wesbecker, he hadn't thought about it, he hadn't prepared. 11 And I have a feeling that all of what's going on now has taken 12 place since his deposition. 13 MR. McGOLDRICK: I don't intend to ask him 14 about -- anything about Wesbecker, one. Two, all of these 15 works that he's talking about on violence and aggression is 16 old stuff. He's talked about this lots of times, long ago. 17 He talks about it all the time in his lectures. 18 JUDGE POTTER: But did he talk about it when 19 they took his deposition? 20 MR. McGOLDRICK: He certainly did. And, B, in 21 the disclosures as to what he was going to be, we brought him 22 in precisely to be an expert on this animal work and what it 23 shows in regard to aggression and violence and suicide and 24 everything. 25 Mr. Stopher, do you have the pretrial order? 134 1 MR. MYERS: Judge, he was questioned in his 2 deposition in numerous locations, and particularly beginning 3 on Page 351 on the subject of what animal studies showed on 4 the subject of violence and aggression. 5 JUDGE POTTER: Three-fifty-what? 6 MR. MYERS: -One. 7 MR. McGOLDRICK: Judge, we think it's critical 8 testimony, and we don't think it's a surprise at all to Mr. 9 Smith. 10 MR. MYERS: You can simply look in the index, 11 Judge, and see he was questioned on numerous occasions about 12 the subject of aggression and aggressive behavior and 13 particularly about animal studies that had been done. 14 JUDGE POTTER: (Reviews document) Let's take a 15 ten-minute recess. 16 (BENCH DISCUSSION CONCLUDED) 17 JUDGE POTTER: Ladies and gentlemen, I'm going 18 to take a ten-minute recess. As I've mentioned to you-all 19 before, do not permit anybody to communicate with you on this 20 case and do not discuss it among yourselves. We'll take a 21 recess for ten minutes. 22 (JURORS EXCUSED; HEARING IN OPEN COURT) 23 JUDGE POTTER: Let me just tell you -- 24 Mr. Smith, what do you want to say? 25 MR. SMITH: Again, Your Honor, these references 135 1 that the Witness is making were never disclosed to us in 2 depositions, were never disclosed pursuant to the Court's 3 order. He's talking now about a silver fox study that 4 actually isn't even a study employing Prozac or fluoxetine 5 hydrochloride. 6 JUDGE POTTER: See, this is -- Mr. McGoldrick, 7 this is my problem. I haven't gone back and read the order of 8 July 14th, 1994, but there was an expert witness disclosure -- 9 you can be seated, Doctor, if you want to -- and the first one 10 on the list is Ray Fuller, and it says none of these 11 individuals have been retained by Lilly as an expert witness 12 in this matter; however, each has been involved in the 13 development, testing and approval of the testing of Prozac, 14 and their testimony will relate to the facts surrounding... 15 Testimony could involve certain professional opinions or 16 conclusions which they formed which arise out of their work 17 with Prozac. I mean, these people -- I mean, you know, you've 18 got Greist and all these other people that are going to come 19 in, and this -- Doctor Fuller is probably qualified, probably 20 could have done the research and could express the opinions or 21 can express the opinions, but what I'm hung up on is sort of 22 whether he was disclosed properly. 23 MR. McGOLDRICK: Judge, if I may be heard? 24 JUDGE POTTER: Uh-huh. 25 MR. McGOLDRICK: There is a document called 136 1 Identification of Expert Witnesses, in which all of the 2 potential experts of the company, numbering 14, were listed, 3 including Doctor Greist. 4 JUDGE POTTER: You're looking at something where 5 you're seeing on Page 7? 6 MR. McGOLDRICK: No, sir. I'm looking at this 7 document. Perhaps I have the wrong document. 8 JUDGE POTTER: Okay. Yeah. Okay. I'm looking 9 at something that was filed later, I think. That was in 10 January of '94? 11 MR. McGOLDRICK: It looks like it; yes, sir. 12 JUDGE POTTER: I'm just looking at the fax thing 13 on the top of it. 14 MR. McGOLDRICK: A, he was disclosed then as an 15 expert. 16 JUDGE POTTER: Right. 17 MR. McGOLDRICK: It's part of his job to do all 18 this work. He is a scientist. 19 JUDGE POTTER: Right. 20 MR. McGOLDRICK: He's a basic scientist who does 21 that research. And it's part of his job to know about the 22 medicine, to know the effects of the medicine, to know its 23 behaviors in animals' aggression or not aggression; that's one 24 of the things he's done, and he's testified to that. 25 Furthermore, I don't think, with respect, for one minute that 137 1 Mr. Smith is surprised at all that Doctor Fuller is here to 2 testify about these subjects. 3 I guess my last point for this moment is that 4 Doctor Fuller is our witness to talk about these subjects. Of 5 course, we'll have other witnesses who will talk about Joseph 6 Wesbecker and who will talk about clinical studies and other 7 things of that sort. But with respect to this large body of 8 scientific evidence that supports Prozac not being related to 9 aggression, this is our man, and I think that's well known. 10 Mr. Smith interrogated him about the subjects of violence and 11 aggression in his deposition. Mr. Smith was not apparently 12 misled. He knew we were bringing him in as an expert in that 13 respect, and he questioned him about it in the deposition. If 14 he didn't ask him about everything, well, I can't help it. 15 MS. ZETTLER: The Court order says differently, 16 Your Honor. 17 MR. STOPHER: Your Honor, can we have only one? 18 MS. ZETTLER: Sorry. I saw two or three of you 19 up here before. I'm more familiar with the court order, 20 though, Your Honor, because Mr. Smith was not involved with 21 the case at the time. 22 MR. STOPHER: Your Honor. 23 JUDGE POTTER: Wait. Wait. I have not gone 24 back and read the court order, but there was a response filed, 25 and I remember some kind of discussion about what kind of 138 1 expert opinions these people were going to express, and it was 2 kind of... 3 MR. SMITH: If you recall, Your Honor, the Court 4 said if they intend to elicit any particular opinion not 5 covered by counsel for the plaintiff, then they must elicit it 6 at the time. The fact is, Doctor Fuller's testified he didn't 7 do any studies while at Lilly to examine the issue of whether 8 or not Prozac caused violent-aggressive behavior in humans or 9 animals. 10 JUDGE POTTER: Where does he say that? 11 MS. ZETTLER: Page 349. I'll get it. 12 MR. McGOLDRICK: The point we advance is that 13 Doctor Fuller is indeed a great expert in this field. 14 JUDGE POTTER: That's not the issue. 15 MR. McGOLDRICK: And that this work is widely 16 known, known to Mr. Smith, no surprise, and that Doctor Fuller 17 does this as part of his work and ought to be allowed to tell 18 the jury, if we're trying to get to the truth, what it is that 19 he knows on the subject. If there was some unfairness in it 20 it would be a different subject; I just don't respectfully see 21 it. 22 MR. SMITH: Sir, 349 at the bottom of the page. 23 JUDGE POTTER: (Reviews document). 24 MR. SMITH: Again, Your Honor, we would point to 25 Page 157 where we asked him specifically. 139 1 JUDGE POTTER: I don't have 157. It must be in 2 a different volume. 3 MS. ZETTLER: I'm sorry. I'll get that. 4 MR. SMITH: We had to break it down into two 5 volumes. I couldn't carry the entire thing. 157. My summary 6 there says Fentress versus Shea Communications. 7 JUDGE POTTER: This is my problem, Mr. 8 McGoldrick, and I haven't gone back and read the order of July 9 17th or 14th, but from reading the response, I'm virtually 10 certain it said identify your experts, give what they're going 11 to say, the subject matter they're going to testify on and the 12 opinions they reach and the summary for the grounds that 13 they're going to reach them and then they went out and took 14 all these people's depositions. There's a list here that says 15 present and former Lilly employees, and it specifically states 16 they will testify and will relate to facts surrounding their 17 work with Lilly, their testing and approval of Prozac and 18 professional opinions, conclusions which they have formed 19 which arise out of their work with Prozac and this accounts 20 for why you listed him on that first sheet. 21 Mr. Smith goes through a deposition with this 22 fellow, and I don't know exactly where it is but what these 23 people meant came up at a pretrial hearing, and my memory 24 would be I said to protect yourself, Lilly, what you need to 25 do, if you're going to get some expert opinions on these 140 1 people, you need on your own cross-examination to get it in, 2 so when they come to trial and express them, you can say he's 3 already said this in his deposition, even though it's not in 4 this pretrial disclosure. And I've got something where Mr. 5 Smith says, April of '94, I guess it was before this expert 6 thing came out. 7 MR. McGOLDRICK: I think it was, Your Honor. 8 JUDGE POTTER: It says, "Your name is mentioned 9 on Page 2 of the expert disclosure. Have you been asked to 10 render any opinions in connection with the lawsuit entitled 11 Fentress versus Shea?" 12 "Not that I remember." Then he goes through 13 this whole thing later on about aggression in animals. The 14 only thing they come up with is Doctor Stark, Slater, whoever. 15 MR. SMITH: Yes. Stark. 16 JUDGE POTTER: So it's not that he isn't 17 qualified. It's not that it wouldn't be helpful to the jury 18 if they had his testimony. And that's the real tug on me is, 19 you know, he's a knowledgeable person. I think the jury could 20 benefit from his testimony. But you-all have experts -- no 21 shortage of experts that are going to say exactly what he's 22 going to say, you know. And I just can't help but believe 23 that if he was -- you know, avowal testimony starts coming in 24 it's going to come out that most of these articles he prepared 25 and read for within the last month or two. 141 1 MR. McGOLDRICK: Perhaps we should have a voir 2 dire on that, Your Honor, because I think -- I know that 3 that's -- that he has read these articles for many years. 4 JUDGE POTTER: He may have. But, I mean, it's 5 just Mr. Smith goes into this thing, he asks the question have 6 you been asked to give an opinion; not that I remember, not 7 that I know of. And then they take him all through his work 8 at Lilly and that sort of stuff, and then you give him this 9 expert witness thing that says it's going to relate to his 10 work at Lilly and opinions he may have formed in connection 11 with his work at Lilly. 12 And I don't know if Mr. Myers was there, but -- 13 or Mr. Stopher, but there was something where Mr. Smith 14 expressed severe concern that this list was going to be kind 15 of like stealth experts. And I don't know any other way to 16 police it other than to make you make certain disclosures and 17 then, you know, limit the Witness. I don't like to do it 18 because I do think it cuts down on information that would be 19 helpful to a jury; however, in this case I'm really not 20 concerned because you have a stable of people that you 21 disclosed to give these opinions. 22 MR. McGOLDRICK: Judge, can I be heard briefly 23 on it? 24 JUDGE POTTER: Uh-huh. 25 MR. McGOLDRICK: A couple of points. First, 142 1 there is in January a disclosure that the man is one of our 2 experts. 3 JUDGE POTTER: Right. 4 MR. McGOLDRICK: Then Mr. Smith takes his 5 deposition. 6 JUDGE POTTER: Right. 7 MR. McGOLDRICK: Then it's only thereafter that 8 there is this other -- I must say, I may not be the best 9 person to address this here, others may need to address this 10 part, but there is this other meeting at which what Your Honor 11 described occurred. 12 JUDGE POTTER: He specifically brought up the 13 concern that these people listed here were going to be used to 14 wheelbarrow in a lot of stuff that he didn't have time to get 15 ready for. 16 MR. McGOLDRICK: When Mr. Smith took Doctor 17 Fuller's deposition, that hearing and whatever rulings 18 occurred at that time had not occurred, one. 19 JUDGE POTTER: That's right. 20 MR. McGOLDRICK: He was not relying on it at the 21 time he took the deposition, one. 22 JUDGE POTTER: Right. 23 MR. McGOLDRICK: Secondly, this Witness is the 24 witness in our list of expert witnesses and at Eli Lilly who 25 is, as part of his job -- it's not that he goes out and we 143 1 give him some list of Mr. Wesbecker's conditions and say will 2 you review this. It is part of his job to know about what 3 happens when animals take fluoxetine. He -- whatever happens 4 at Lilly he knows about, whatever happens in the world 5 literature on this subject he's supposed to watch. He does. 6 As a result of that, he can report on that as part of his job 7 functions. That, in itself, is not expertise, but I would 8 respectfully submit that the type of expertise which we're 9 talking about here and which I think fits exactly with Your 10 Honor's second order, as I understand it, is just that. As 11 part of his job he's a great expert, and as part of his job he 12 exercises that expertise and it's not so that, A, he is not an 13 expert witness in that kind of category; he's just reporting 14 on what he knows and what he's learned as part of his work, A. 15 B, I don't see it with respect as being stealth or any 16 surprise. 17 When Doctor Fuller was asked the question 18 whether he'd been -- given an opinion, was going to be asked 19 to give opinions in connection with that, I think he was being 20 asked whether he was being asked to give opinions about Mr. 21 Wesbecker, and he's not giving opinions about Mr. Wesbecker. 22 I haven't mentioned Mr. Wesbecker and don't plan to. He's 23 going to report on what the science of the world is, just the 24 way others did, and I don't think, respectfully, that it's any 25 surprise or stealth in any respect. 144 1 MR. MYERS: If the Court simply looks at the 2 beginning at Page 157 and going over to Page 162, there was a 3 long discussion among the lawyers about the nature of any 4 testimony that Doctor Fuller would give in this case and the 5 fact that while he was not a Wesbecker-specific witness that 6 he would give testimony. 7 MR. SMITH: I asked him what his opinion was and 8 then Mr. Myers interposes an objection. 9 JUDGE POTTER: Let me see. 10 MR. McGOLDRICK: Mr. Myers was there. Maybe -- 11 JUDGE POTTER: Wait. Wait. Wait. Let me read. 12 This is a thing I've read time and time again. (Reviews 13 document) I have read his deposition, Pages 157 through -- I 14 guess it's 162, for the second or third time, and based on 15 that, based on my memory of prior orders, I'm going to limit 16 his testimony to basically what he's done and, you know, 17 opinions peripheral to his development of the thing and what 18 goes on within Lilly. And they did get into some other things 19 in there, but sort of this broad review of the literature, 20 some of those things he's citing you-all mentioned last night 21 weren't even published until a couple of months ago, or maybe 22 I misunderstood the dates on them. 23 MR. McGOLDRICK: I realize I may be trying the 24 Court's patience, but I do want to mention two other things. 25 One, Doctor Fuller, I believe, wrote memoranda on exactly what 145 1 I'm going to ask him about, in 1990, and if there's anything 2 more recent that somehow shouldn't be part of this for some 3 reason, we can delete that. But Doctor Fuller was deposed on 4 exactly these subjects and it was produced to the Plaintiffs. 5 JUDGE POTTER: If he made a mistake in it I can 6 trust you he's going to see it back in his face today. I 7 mean, go ahead. 8 MR. McGOLDRICK: The second point I'd have is 9 that Your Honor says that he can be interrogated about what he 10 did at Lilly and so forth, but it seems to me that on the 11 issues of negligence or reasonableness of conduct in any 12 fashion, Lilly's awareness of what the world literature was, 13 its own knowledge, goes to the question of negligence or not, 14 and his knowledge of what that is in this respect is very much 15 Lilly, that he's there looking at it for Lilly. 16 JUDGE POTTER: If you want to limit him to 17 things -- how many of the things he's going to report on were 18 published before 1989, not very many. The state of the art 19 really I don't think has been an issue in this case so far. I 20 mean, maybe it will be at some point. But Lilly has sort of 21 taken the posture that Prozac doesn't cause this problem and 22 therefore we're not saying, you know, we did the best we could 23 but we missed. 24 MR. McGOLDRICK: I'm not saying that, Your 25 Honor. We think that's true, always been true, true today. 146 1 My point is slightly different, and it is that the argument of 2 the Plaintiffs is that Lilly, in 1989 or before, should have 3 done things, other testings, other warnings, all kinds of 4 things, based upon what it knew or should have known. Doctor 5 Fuller is here in part to testify about what Lilly knew at 6 that time. 7 JUDGE POTTER: Mr. Smith, if he wants to testify 8 -- maybe you wouldn't even object to that. But if he wants to 9 testify in 1989, I had never seen the report; I didn't see 10 this; I didn't know that, I think you might have a different 11 opportunity. I mean, your objections might be treated 12 differently. 13 MR. SMITH: I don't think that's what he's 14 intending to do. What he's talking about is a silver fox 15 study that was done I think subsequent to 1989, I think 1992 16 or '91, a study that was done after this occurred. 17 MR. McGOLDRICK: Judge, I believe we should be 18 entitled to interrogate about that, but we're talking about a 19 whole range of things that Mr. Smith knows he has in his early 20 memoranda which relate to some things, which there's a review 21 paper from 1987. This one is 1991, but 1977, 1978, 1985, 22 1983; this is key work, 1984, 1984. Mr. Smith -- I'm not 23 going to go through them all. Mr. Smith is here to tell the 24 jury that we acted improperly in light of what was known or 25 should have been known. We can -- we ought to be able to 147 1 testify as to what was known, and it's good, and that's why 2 Mr. Smith doesn't want it. 3 JUDGE POTTER: Well, I don't want to get into 4 who wants what and why, but there is a certain set of orders 5 that were in effect about what people were supposed to do 6 before they wanted to call witnesses. And there have been 7 very few pretrial orders in this case, and that has maybe 8 worked to some people's detriment at some time and other 9 people's detriment at the other time. But if this guy was 10 going to come in as one of your major expert witnesses, it 11 seems like to me he deserves more than one line in the expert 12 disclosure and more in his deposition than "I've never heard 13 of Fentress versus Shea. Nobody's asked me about any opinions 14 in it." 15 As a matter of fact, in the pages I read, I 16 don't know if Ms. Zettler was correctly quoting my orders or 17 not, but she put you-all on clear notice that if he didn't 18 answer the question and you-all didn't elicit additional 19 information from him, they were going to bring this issue up 20 at trial. That was in that 167 to 168 or whatever it was. It 21 sounds like a lot of lawyers' sidebar carping about something, 22 but, I mean, you-all were put on notice that she was going to 23 raise this issue and then to come in here now and say this is 24 one of your most crucial witnesses... 25 I mean, I don't know who Doctor Greist is, but 148 1 he's got four pages devoted to him; Mr. Rothschild has three 2 pages, you know, of what they're going to say. And it puts 3 these people on notice when they go to take their deposition 4 that this is the topic the man's going to be on, explored on 5 this, and Mr. Fuller is listed here. But everything seems to 6 say it's going to be about what he did at work and his 7 connection with the Lilly process of developing Prozac. 8 MR. McGOLDRICK: This is what he does at work, 9 Judge, this is exactly what he does. 10 MR. MYERS: They examined him on the subject 11 matter, Judge, Page 351 to 357 or 358. 12 JUDGE POTTER: Is that the Slater thing? 13 MR. MYERS: The Stark thing, and then on 357 14 elected to limit the inquiry to studies done by Lilly. They 15 were the ones that asked the question. 16 MR. SMITH: The point is, if you -- 17 JUDGE POTTER: Wait, Mr. Smith. I can only read 18 or listen. (Reviews document) Okay. I'm going to limit his 19 testimony. What you can do is put it in by avowal after we 20 get through today or get through tomorrow. 21 MR. McGOLDRICK: I don't want to before the jury 22 run afoul of Your Honor's order. Am I going to be permitted 23 to ask the man the import of what the company knew in the 24 studies that existed before -- the date is September 1989? 25 MR. SMITH: September 14th, 1989. 149 1 JUDGE POTTER: I mean, if he's talking about 2 what he did at work and what they found and why they did this, 3 I can't imagine I'm going to have any -- sustain any of 4 Mr. Smith's objections. But if he starts -- I mean, if he 5 objects to something before that, I'll just have to hear his 6 reasons for it. 7 MR. McGOLDRICK: All right, sir. 8 (HEARING IN OPEN COURT CONCLUDED) 9 SHERIFF CECIL: The jury is now entering. All 10 jurors are present. Court is back in session. 11 JUDGE POTTER: Please be seated. 12 Doctor, I remind you you're still under oath. 13 Mr. McGoldrick. 14 MR. McGOLDRICK: Thank you, Your Honor. 15 Doctor Fuller, before the break, we were talking 16 about a subject. I'd like to turn now to this question: Was 17 it part of your job at Eli Lilly and Company to monitor and be 18 aware of work being done, in animals and otherwise, with 19 respect to aggression and violence? 20 A. Yes. It was part of my job to be aware of all 21 work, I guess, all research being done on serotonin in 22 general, but certainly on fluoxetine. As I mentioned, we 23 provided fluoxetine to a lot of investigators for experimental 24 studies, and certainly my responsibility was to keep abreast 25 of the findings that they generated in those studies. 150 1 Q. And were -- I don't want to make you be 2 immodest, but were you one of the company's experts in that 3 subject internally? 4 A. I certainly was more devoted to it than anyone 5 else, I think, yes. 6 Q. And as part of your work, did you keep aware of 7 the published scientific literature on the subject of the 8 effects of serotonin, elevated or reduced, and Prozac? 9 A. Yes, sir; I did. 10 Q. And their effects on aggressiveness and violent 11 behavior? 12 A. Yes, sir. 13 Q. You read the articles on that as part of your 14 job? 15 A. I did. 16 Q. You were in many ways how Eli Lilly knew about 17 that? 18 A. That would -- I felt that was my responsibility, 19 sir, yes. 20 Q. Others at the company may have done it, but you 21 certainly did it and it was your responsibility? 22 MR. SMITH: Objection, leading, Your Honor. 23 JUDGE POTTER: Overruled. 24 Q. Is that right, sir? 25 A. Yes, sir. 151 1 Q. All right. Now, I'd like to -- and I want you 2 to be careful in answering the question. I want you to focus 3 now on the work that had been done either at Lilly or by 4 investigators to whom Lilly provided the medicine or by anyone 5 in the world doing science about aggression and Prozac and 6 serotonin before September of 1989. Do you understand that's 7 the period of time I want you to focus on? 8 A. Yes, sir. 9 Q. All right. Now, in that period of time, was 10 there evidence, that you were aware of as part of your job, 11 about aggression and violent behavior related to serotonin and 12 Prozac? 13 A. Yes, sir. There was a good deal of such 14 evidence. 15 Q. All right. And would you tell the jury about 16 that evidence? What was it? 17 A. Could you repeat the question? Are you asking 18 specifically about Prozac or more broadly with regard to 19 serotonin? 20 Q. Both, really, as long as it's before September 21 of 1989. 22 A. Well, there certainly were studies done by a lot 23 of investigators which related to the role of serotonin in 24 aggressive behavior. There were studies which involved 25 manipulating the serotonin system by increasing or decreasing 152 1 serotonin function, either by means of drugs or by some other 2 procedures. And those studies showed -- without exception, so 3 far as I can remember -- that any treatment which increased 4 serotonin function decreased aggressive behavior, and any 5 treatment which decreased serotonin function increased 6 aggressive behavior. 7 In addition to those studies, there were other 8 kinds of studies which linked serotonin to aggression, studies 9 in which the concentration of serotonin in the brain or the 10 concentration of its metabolite, 5-HIAA, in the cerebrospinal 11 fluid, were measured in animals and also in humans who showed 12 aggressive behavior. And, again, in general, the findings 13 were always that a lower amount of serotonin in the brain 14 tended to be associated with increased aggressive behavior and 15 conversely. And these are studies that have been published by 16 many investigators and reviewed by experts in the field who 17 have generally written that this is a very consistent finding, 18 that serotonin is related to aggressive behavior in that way; 19 the more serotonin, the less aggression and conversely. 20 Now, specifically with regard to Prozac, or 21 fluoxetine, aggressive behavior has been studied in laboratory 22 animals in a lot of different ways. There are experts in this 23 area who have devised ways of scoring and quantitating 24 aggressive behavior in mice, rats, hamsters, monkeys and other 25 species. The first studies that I remember learning about 153 1 with regard to fluoxetine, or Prozac, were done in mice, male 2 mice which had become aggressive as a result of isolation from 3 other mice. That happens with some species, when they are 4 isolated they become aggressive. These male mice, when 5 treated with fluoxetine, or Prozac, showed less aggression 6 than they otherwise showed. Those data were reported to me by 7 Doctor Richard Katz, who is at the University of -- was at the 8 University of Michigan Mental Health Research Institute, who 9 obtained fluoxetine from us for the purpose of doing those 10 studies. 11 Q. Excuse me. You're about to go to another item, 12 Doctor? 13 A. Yes, sir. 14 Q. Do you remember when that work, that scientific 15 work was done? 16 A. That work was reported to me in 1977. 17 MR. McGOLDRICK: If Your Honor please, I wonder 18 if I might use the easel and make a note of some of these 19 things for reference? 20 JUDGE POTTER: Sure. 21 MR. SMITH: May we approach, Your Honor? 22 (BENCH DISCUSSION) 23 MR. SMITH: What he's going to do now is just 24 handwrite that. 25 JUDGE POTTER: Mr. Smith, you know, this guy is 154 1 testifying that somebody from Michigan gave me this stuff and 2 my job in 1977 -- if he wants to write up on the bulletin 3 board '77, mice study; '88, rat study... Because this is 4 entirely different. This is this guy telling about what went 5 on when he was there, and he may write some of this stuff up. 6 (BENCH DISCUSSION CONCLUDED) 7 Q. Can you see this, Doctor? 8 A. I think so. 9 Q. All right. That was in 1977? 10 A. Yes, sir. 11 Q. And where was Doctor Katz? 12 A. University of Michigan Medical School. 13 Q. And that study involved a particular kind of 14 mice? 15 A. These were aggressive mice because they had been 16 isolated. 17 Q. I think you explained it, but could you just 18 tell us a little bit more about that? These mice, what do you 19 do, you take them away from their friends and they get 20 aggressive? What happens? 21 A. That's correct. They're simply kept in 22 isolation away from any other mice for a period of some weeks, 23 and then when put back with another male mouse they are 24 aggressive, they fight, they attack that other mouse. 25 Q. And how were they studied again? 155 1 A. They were given fluoxetine, and the findings 2 were that fluoxetine reduced that aggressive behavior. Doctor 3 Katz also did other work about that same time with other drugs 4 that decreased serotonin function, and they had just the 5 opposite effect, they increased that aggressive behavior. 6 Q. So, first of all, he tried giving them Prozac 7 and he watched what happened to their behavior? 8 A. Yes, sir. 9 Q. And then he gave them drugs that decreased 10 serotonin function and he watched their behavior? 11 A. That's correct. 12 Q. The ones with the Prozac, the aggression was 13 down? 14 A. That's correct. 15 Q. The ones with the serotonin reducing drugs, the 16 aggression was up? 17 A. That's correct. 18 Q. Now, tell me, if you can, Doctor, how do you 19 know whether a mouse is aggressive or not? 20 A. Well, these mice were simply observed. When 21 another mouse was put in their presence, they would attack 22 that mouse. And Doctor Katz simply scored the number and 23 frequency of those attacks. 24 Q. And is this the kind of research that is done 25 typically with medicines on this kind of subject? 156 1 A. That's correct. 2 Q. All right. Now, I interrupted you. You were 3 about to tell the jury about another piece of science during 4 this period we're talking about. 5 A. Well, staying chronological, the next findings 6 that I remember being aware of were in a study done by a group 7 of investigators in New York, at Columbia University and at 8 Albert Einstein College of Medicine. This was a study in 9 rats, and it was a study in a type of rat called muricidal 10 rats. Muricidal simply means mouse killing. There are 11 certain strains of rats that will spontaneously kill mice. If 12 you put a mouse into a cage with this rat, the mouse will be 13 dead very soon. The rats are aggressive; they will kill mice. 14 And this kind of muricidal or mouse-killing behavior has been 15 very frequently studied by investigators who are interested in 16 aggressive behavior and the influence or neurotransmitters on 17 that behavior. 18 This group, the first author I believe was 19 Doctor Judith Gibbons, reported in 1978 at a neuroscience 20 meeting that fluoxetine decreased this aggressive behavior in 21 these rats. She also observed that other drugs which 22 increased serotonin function, such as tryptophan, also 23 decreased that aggressive behavior; whereas, drugs which 24 reduced serotonin synthesis, like para-chlorophenylalanine, 25 had just the opposite effect; they increased aggressive 157 1 behavior. So in these muricidal rats, fluoxetine had the same 2 effect that it had in the isolated mice; it reduced aggressive 3 behavior. 4 Q. And what year was that work done, Doctor? 5 A. That was reported in 1978. 6 Q. That's done where? 7 A. That was done in New York, at Columbia 8 University and Albert Einstein. 9 Q. And I don't want to repeat everything you said 10 here but just -- 11 A. Well, the key difference is that this was not in 12 rats. One key difference, this was in rats. 13 Q. In muricidal rats? 14 A. Muricidal rats; that's correct. 15 Q. Is this a special species of rat? Do all rats 16 do this? 17 A. No. Not all rats do this; only some strains of 18 rats do it. But, as a matter of fact, in rats that are not 19 normally muricidal, they can be made to be muricidal in one of 20 several ways. Again, this can be induced by isolation of 21 those rats; it can be induced by a surgical lesion of a part 22 of the brain called the olfactory bulb; it can be produced by 23 an electrolytic lesion in the part of the brain called the 24 raphe nucleus, which is a place where there's a lot of 25 serotonin neurons in the brain, and it can be induced by the 158 1 treatment of rats with para-chlorophenylalanine, which 2 inhibits serotonin synthesis. So after this study was done in 3 1978, in spontaneously muricidal rats -- 4 Q. These are rats -- spontaneously means they're 5 just that way naturally? 6 A. That's right. This is a strain of rats that is 7 just mouse killing, when given a chance. There have also been 8 studies done by several other groups of investigators in rats 9 that are not normally muricidal but were made muricidal by one 10 or more of those four means that I listed. 11 Q. Let's just stay with this one for a moment, 12 Doctor. In this one they gave Prozac to normally 13 mouse-killing muricidal rats -- 14 A. That's correct. 15 Q. -- and what happened? 16 A. They stopped killing mice. They became less 17 aggressive. 18 Q. That was with fluoxetine, Prozac? 19 A. That's right. 20 Q. All right. Now, was there any other evidence, 21 during this period of time that we're talking about, of the 22 relationship between serotonin, Prozac, and aggression? 23 A. Yes. There were a series of studies done by 24 Professor Valzelli at the University of Milan in Italy; he was 25 one of the world's experts in the study of aggressive behavior 159 1 in laboratory animals. And he did some of the studies that I 2 mentioned, which involved muricidal behavior in rats that were 3 not otherwise muricidal but were made muricidal by one of 4 those treatments. 5 Q. He did different studies? 6 A. Studies in different rats in which he caused 7 them to be muricidal and then looked at the effect of 8 fluoxetine on that muricidal behavior. 9 Q. All right. Let's make a note of that. That's 10 Professor Valzelli, and that is in Milan, Italy, did you say? 11 A. Yes, sir. 12 Q. And he took rats that were not normally 13 mouse-killing rats? 14 A. Yes, sir. 15 Q. And by some differing methods he made them into 16 that? 17 A. Yes. 18 Q. Just quickly again, how did he do that? 19 A. He did that by giving para-chlorophenylalanine, 20 which is a drug that inhibits serotonin synthesis. 21 Q. So it would be right to say that he made the 22 rats muricidal; is that right, sir? 23 A. That's correct. He studied both rats that are 24 spontaneously muricidal and other rats that he made muricidal. 25 He studied both kinds of animals. 160 1 Q. And then what did he do next? 2 A. Then he gave fluoxetine. And the effect in both 3 cases -- 4 Q. Excuse my back. 5 A. That's all right. 6 Q. And what happened? I'm sorry. 7 A. The effect in both cases was a reduction in the 8 aggressive behavior. 9 Q. Was this work reported in the scientific 10 literature? 11 A. Yes, it was. 12 Q. Was it peer reviewed? 13 A. Yes, it was. I feel sure it was. 14 Q. What else is this along this line, Doctor, can 15 you tell us? 16 A. Another expert in the world in the study of 17 aggressive behavior in rats was the late Professor Paul Mandel 18 at The University of Strasbourg in France. He did studies 19 also with fluoxetine in mice that had been made muricidal by 20 different methods, the surgical lesions that I mentioned. And 21 he gave those rats fluoxetine, as well, along with other drugs 22 that affected serotonin function, and what fluoxetine did was 23 to reduce the aggressive behavior in those muricidal rats. 24 Q. That's -- we'll try to do this quickly -- 25 Professor Mandel, and he's in France somewhere? 161 1 A. He was at The University of Strasbourg; he is 2 now dead. 3 Q. And when was that done? 4 A. That was reported in the mid 1980s. 5 Q. And, once again, what did he do? 6 A. He made the rats muricidal by different methods, 7 including electrolytic lesions of the raphe nuclei, which is a 8 part of the brain that is particularly rich in serotonin 9 neurons. 10 Q. Are these muricidal rats a frequent way 11 scientists study aggression? 12 A. Yes. They are probably one of the very most 13 common ways of studying aggressive behavior. 14 Q. It would be unethical to try to make people 15 aggressive? 16 A. Yes, sir. 17 Q. So you don't do those kinds of experiments? 18 A. That's right. 19 Q. You use animals. And he made them muricidal by 20 a different method than Professor Valzelli and he used -- 21 A. He used fluoxetine to treat those rats. 22 Q. And the result was? 23 A. The result was a decrease in aggressive 24 behavior. 25 Q. Anything else along that line, Doctor? 162 1 A. Well, yes. Professor Mandel's group actually 2 did these studies over a period of several years, and they -- 3 in addition -- okay, you have it correct. They made muricidal 4 rats. They made muricidal rats by different methods; they 5 lesioned the raphe, and they also cut the olfactory bulb, but 6 that's essentially correct. 7 Q. Got anything else along that line, sir? 8 A. There have certainly been other studies of 9 fluoxetine in aggressive behavior of different sorts. I'm 10 trying to remember the dates. You specifically asked me to 11 restrict my comments to things that happened before -- 12 Q. September 1989. 13 A. -- September 1989. 14 Q. If you want to refer to any of your notes, you 15 can. What is a review article? Let me just ask you that. 16 A. A review article is a -- is a -- in this context 17 a scientific paper which simply analyzes all the results on a 18 particular subject that have been published and synthesizes 19 those into some sort of analyzed pattern of what the findings 20 have been. 21 Q. And is a review article a well-known thing in 22 scientific literature and science in general? 23 A. They're very useful in scientific literature 24 because they collect together the literature on a particular 25 subject so that an individual scientist doesn't have to dig 163 1 back through all of those individual papers. 2 Q. Did a man named Olivier write a review article 3 on this subject of serotonin and its effects and other effects 4 on aggression? 5 A. Yes, he did. Doctor Baron Olivier, who is from 6 the Netherlands, has studied aggressive behavior extensively 7 for years, and he has published not only his extensive 8 research findings but he has written review articles on the 9 subject, as well. 10 Q. Let me call your attention to -- in the year 11 1987, did he write a review article? 12 A. Yes. I remember the paper you're referring to. 13 It was published, I believe, in a book that came out in 1987, 14 and it summarized a large body of evidence that related to 15 serotonin and aggression, including studies on fluoxetine but 16 including studies on other kinds of drugs that modify 17 serotonin function, as well. 18 Q. Could you, by referring to your notes, if 19 necessary, if you don't remember each one, tell us what the 20 key points of -- who is it, Professor Olivier? 21 A. Olivier. 22 Q. And he is in what country? 23 A. He is in the Netherlands. He reviewed studies 24 that had been done in mice and in rats and in a variety of 25 different aggressive models, including the muricidal rats that 164 1 I mentioned, the isolated mice that I mentioned. Other kinds 2 of models that are used in the study of aggressive behavior 3 include maternal aggression; mother rats will become very 4 aggressive when they think their baby rats are in danger. 5 That type of aggressive behavior has been studied. There's 6 foot-shock induced aggression. If you deliver a painful foot 7 shock to a rat, that rat will aggress upon another rat or an 8 inanimate object even that's in the cage. So that there are 9 methods of that sort which have been used by investigators to 10 study aggressive behavior and the role of particular brain 11 neurotransmitters in controlling that behavior. 12 Q. Doctor -- I've forgotten his name already. 13 A. Olivier. 14 Q. He looked at various reports, including 15 aggression caused by foot shock, maternal aggression. And is 16 that just mother rats being very aggressive in protecting 17 their young? 18 A. That's right. 19 Q. And other kinds? 20 A. Yes. Another type of aggression that he 21 examined was called territorial aggression. 22 Q. What's that? 23 A. Animals like hamsters or rats, when they live in 24 a cage, they consider that cage to be their castle, so to 25 speak, and whenever an intruder hamster or rat is placed into 165 1 the cage with them, they will immediately try to drive the rat 2 out or the hamster out and attack him and fight him. 3 Q. Those are the kinds he studied? Muricidal, too? 4 A. Muricidal, also. 5 Q. And with all of these different incidences of 6 aggressive behavior, what was it that the studies showed? 7 A. Well, one of the principal conclusions from that 8 review is that serotonin was a very important transmitter in 9 influencing aggressive behavior and that drugs which increased 10 serotonin function reduced aggressive behavior. Fluoxetine 11 was one of those drugs, and there were some others that were 12 included in the various studies that were discussed. 13 Q. So, serotonin was enhanced -- I'll just say 14 "up." Serotonin was up, the aggression was down? 15 A. That's correct. 16 Q. And in some of those studies they used Prozac? 17 A. That's correct. 18 Q. Not all? 19 A. Not all, no. 20 Q. Some of them they just tested the aggressive 21 behavior and looked at the serotonin levels? 22 A. That's correct. 23 Q. Anything else that Doctor Olivier reported? 24 A. I think that's the essence of that paper that's 25 particularly relevant to today's discussion, yes. 166 1 Q. All right. Now, let me ask -- turn to a 2 slightly different subject, unless there was anything else 3 that you particularly wanted to -- well, strike that. I'll 4 ask you a different question. 5 Up to September of 1989, which is the purpose of 6 my present question, what was the state of the scientific 7 literature with respect to serotonin, Prozac and aggression; 8 that is to say, was it pretty strong evidence one way or the 9 other, was it weak, what was it like? 10 MR. SMITH: Can we have a clarification on 11 whether or not that's animals or humans, Your Honor? 12 JUDGE POTTER: I guess he's talking about 13 everybody. 14 Go ahead. 15 Q. Pre-'89, I'm talking about everybody. 16 A. Perhaps I should just clarify, with respect to 17 that comment, that there have been a lot of studies done in 18 humans as well as in animals with regard to aggressive 19 behavior. And the findings have generally been in very good 20 agreement, and that agreement has been noted by a number of 21 investigators. The kinds of studies that have been done in 22 humans, however, have often been somewhat different than the 23 kinds of studies done in laboratory animals. For example, in 24 humans, a lot of studies have been done with regard to the 25 serotonin metabolite in cerebrospinal fluid, so that lower 167 1 levels of that serotonin metabolite tend to be associated with 2 aggressive, impulsive, hostile behavior. 3 Q. Could I just stop you just so we understand 4 that. You say that in humans something has been associated 5 with aggressive behavior. What? 6 A. A decreased level of the serotonin metabolite in 7 the cerebrospinal fluid. 8 Q. All right. So, I just want to take it step by 9 step. In those kinds of scientific looks, scientists looked 10 at the spinal fluid of certain kinds of persons? 11 A. That's right. 12 Q. And they tested the spinal fluid to see whether 13 this metabolite of fluoxetine -- or, excuse me, of serotonin 14 was there and in what levels? 15 A. Correct. 16 Q. Now, that metabolite is called 5-HIAA? 17 A. That's the abbreviation for it, yes. 18 Q. All right. And that is a breakdown -- something 19 the body breaks serotonin down into? 20 A. That is correct. 21 Q. And so are those levels pretty good measures of 22 what the serotonin level is in the person's brain? 23 A. Yes. It's the only index one has available to 24 assess serotonin function in the human brain while the human 25 is still living. 168 1 Q. And what did those tests show about whether 2 people with high or low serotonin were more or less 3 aggressive? 4 A. The people who were aggressive or violent or 5 impulsive in their behavior tended to have decreased amounts 6 of that serotonin metabolite in their cerebrospinal fluid, 7 which was interpreted as meaning that they had reduced 8 serotonin function. And that, therefore, would be in good 9 agreement with the data from the extensive animal studies, 10 which also suggested that a reduced amount of serotonin 11 function was associated with aggressive behavior. 12 Q. Were these kinds -- this kind of scientific 13 study, was that published? 14 A. Yes. 15 Q. In the peer-reviewed scientific literature 16 available to scientists? 17 A. Yes, sir. 18 Q. Now, again, by September of 1989, was the 19 science that the world knew in agreement on the effect of 20 serotonin and fluoxetine on aggressive characteristics? 21 A. I think it was. 22 Q. And what was the scientific view at that time? 23 A. The view was that a decrease in serotonin 24 function might be a cause of aggressive behavior, and that 25 increasing serotonin function by means of a drug such as 169 1 fluoxetine was a way of decreasing that aggressive behavior. 2 Q. Okay. 3 Judge, I'm going to make a slight shift here. I 4 know it's a little early, but we started a little early. 5 Could I have our break now? 6 JUDGE POTTER: Okay. Sure. 7 Ladies and gentlemen of the jury, I'm going to 8 take the afternoon recess. As I've mentioned to you-all 9 before, do not let anybody communicate with you on this case. 10 Do not discuss it among yourselves. We'll take a 15-minute 11 recess. 12 (RECESS) 13 SHERIFF CECIL: The jury is now entering. All 14 jurors are present. Court is back in session. 15 JUDGE POTTER: Please be seated. 16 Do you want to go ahead -- I can't tell how bad 17 it is out there. Apparently there's an air leak or something, 18 so we'll get it. I think heating and air-conditioning is 19 probably the only trade we don't have on the jury. What kind 20 of construction business is your husband in, Ms. Felker? 21 JUROR FELKER: Home improvement. 22 JUDGE POTTER: He's not heating and 23 air-conditioning? 24 JUROR FELKER: No. 25 JUDGE POTTER: Doctor, I'll remind you you're 170 1 still under oath. 2 Q. Doctor, before the break, I had been asking you 3 about studies that had been done relating to aggression before 4 September 1989, and there was one which I don't think I asked 5 you about, and that was work done by, of all people, Stark, 6 Fuller and Wong. Could you tell me a little bit about that? 7 A. Well, Paul Stark -- Doctor Paul Stark, who is a 8 neuropharmacologist, did some studies of the very same type 9 that I have described to you in muricidal aggression in rats 10 at Lilly, as a matter of fact. And what Doctor Stark showed 11 is that doses of fluoxetine which we had shown inhibited 12 serotonin uptake in rats did suppress muricidal aggressive 13 behavior in rats, exactly the same findings as the other 14 investigators whose studies I did describe. 15 Q. So this was essentially confirming work? 16 A. That's correct. It actually was done before 17 some of those studies, but it was done after the initial study 18 that had been reported by Doctor Gibbons. 19 Q. This was done at Lilly, and you again used this 20 muricidal rat model? 21 A. That's correct. 22 Q. And that was about what year? 23 A. We actually published that in 1985; it was done 24 sometime before that. 25 Q. Okay. And you administered Prozac? 171 1 A. Yes, sir. 2 Q. And you found? 3 A. A decrease in the aggressive behavior. 4 Q. All right. And, Doctor, let's turn to another 5 side of this. As part of your duties at Eli Lilly and Company 6 in the study of serotonin function and Prozac and 7 aggressiveness, did you or Lilly provide to scientists who 8 were independent of Lilly the wherewithal, the Prozac, the 9 fluoxetine, to do their studies? 10 A. Yes, we did. Any requests from a qualified 11 scientist who wanted to do experiments in laboratory animals 12 with fluoxetine, we provided the material for them to do that. 13 Q. And when you did that, was it part of your job 14 to interact with those scientists and monitor what was being 15 done and learn what their results were? 16 A. Not necessarily to interact with them during the 17 course of their studies, but certainly to learn what their 18 results were, if at all possible, yes. 19 Q. And these scientists were completely independent 20 of Eli Lilly? 21 A. That's correct. 22 Q. And did you indeed monitor what happened? 23 A. Yes. We tried. We got all the results we could 24 get back from investigators and, as I mentioned, Doctor Katz, 25 for example, had supplied us with the information that I 172 1 mentioned earlier. He never actually published those data. 2 Many other investigators, when they prepared a manuscript for 3 publication they would provide us with a copy in advance of 4 that publication. 5 Q. And this was part of your job, to know what was 6 happening with this medicine? 7 A. That's correct. 8 Q. So let me turn to some of those examples, if I 9 have them right here, of work where you provided the 10 fluoxetine to the investigator and ask you about some of 11 those. Let's take -- just pick one, work by Doctor Wagner. 12 Do you recall that work? 13 A. This is Doctor Wagner -- yes, Doctor Wagner at 14 Rutgers University. 15 Q. And did he do some work where you provided 16 fluoxetine to him? 17 A. Yes, he did. 18 Q. Was he studying aggression? 19 A. Yes, he was. 20 Q. And when did his work get done? 21 A. It was done more recently. I could refer to my 22 notes and tell you the year it was published. 23 Q. Fine. 24 A. It was published in 1993. 25 Q. And what did he find? 173 1 A. Doctor Wagner was studying aggressive behavior 2 in mice, but aggression that was induced now by alcohol. 3 Alcohol would cause the mice to become aggressive. And he 4 studied the effects of fluoxetine on that aggressive behavior 5 and found much the same as in these other studies in other 6 models of aggression, that fluoxetine reduced the aggressive 7 behavior. 8 Q. By the way, on some of these earlier things, 9 just to try to save a little time, like Professor Valzelli, I 10 think, and maybe some others, I've just been putting up one 11 number, No. 3 for Professor Valzelli, did he publish more than 12 one paper? 13 A. Yes. They actually -- both of those groups on 14 that page -- 15 Q. Professor Mandel and Professor Valzelli? 16 A. -- have a longstanding interest in aggressive 17 behavior, and they actually did and published a series of 18 studies involving fluoxetine. 19 Q. So though I've just listed it under one thing 20 it's really many studies? 21 A. More than one. 22 Q. And they're published? 23 A. Yes, they are. 24 Q. All right. Now, so this work by the fellow at 25 Rutgers. 174 1 A. Professor Wagner. 2 Q. And he administered alcohol to the rats? 3 A. To mice. 4 Q. And does alcohol in mice make them aggressive? 5 A. Yes, it did. 6 Q. And then what did he do? 7 A. He treated them with fluoxetine, Prozac, and 8 their aggression was decreased. He also gave them -- in 9 addition to Prozac, he gave the very same rats tryptophan, 10 which is the precursor to serotonin, the amino acid that is 11 converted into serotonin. And what he found was that the 12 addition of tryptophan increased the anti-aggressive effect of 13 fluoxetine, which would verify that it was being caused by an 14 increase in serotonin function. If you both increase 15 serotonin production and block serotonin uptake, you get a 16 bigger effect. 17 Q. All right. I'm not going to try and write all 18 that down, but the idea is that he gave them tryptophan, 19 T-R-Y-P-O -- 20 A. -T-O-. T-R-Y-P-T-O-P-H-A-N. 21 Q. And what did that do, again? 22 A. Tryptophan increased the anti-aggressive effects 23 of fluoxetine. 24 Q. And what did that tell us? 25 A. That supported the idea that serotonin was the 175 1 mediator of that reduction in aggressive behavior, because 2 tryptophan increases serotonin formation, fluoxetine blocks 3 serotonin uptake; you put those two actions together, you get 4 a bigger increase in serotonin function and a bigger 5 anti-aggressive effect. 6 Q. All right. And turn to another one. In 1991, 7 Doctor Datla and others, was this in India? 8 A. That was a study done in India. 9 Q. And did you provide the fluoxetine there? 10 A. I believe we did. 11 Q. And what happened there? 12 A. They studied another type of aggressive behavior 13 in rats. This was foot-shock-induced aggression, and that 14 also was decreased by fluoxetine. 15 Q. And that's -- you talked about -- and this was 16 actually in India, the country of India? 17 A. That's correct. 18 Q. And Doctor Datla and others did this foot-shock 19 aggression? 20 A. In rats. 21 Q. In rats. And then used fluoxetine? 22 A. Yes, sir. 23 Q. And what happened? 24 A. Fluoxetine reduced that type of aggressive 25 behavior, just as it had reduced the other types of aggressive 176 1 behavior. 2 Q. I think I'm losing it here. I can't spell 3 anymore. Okay. Now, if I can turn to the next one, I think 4 there was one that was done in hamsters. Do you remember a 5 study of that sort, sir? 6 A. Yes. That's a study that I've been somewhat 7 involved in personally. 8 Q. I'm sorry. I didn't hear you. 9 A. It's a study that I've been somewhat involved in 10 personally. It's a study that has been done primarily by 11 Professor Craig Ferris, who is at the University of 12 Massachusetts. And Doctor Ferris has come to my laboratory 13 and learned the technique of brain microdialysis so that he 14 will be able to measure the extracellular serotonin 15 concentration in those hamsters. We actually measured some in 16 hamsters in my own laboratory and he will continue that work. 17 So I know his work; some of it has been published, some of it 18 has not yet been published. 19 Q. And he's at the University of Massachusetts? 20 A. That's correct. 21 Q. And he has got hamsters? Are these hamsters 22 aggressive? 23 A. These are called golden hamsters, and the type 24 of aggression that he is studying mostly is what I described 25 earlier as territorial aggression, what he calls a resident/ 177 1 intruder model of aggression. He takes male hamsters who live 2 in a particular cage, and he adds another male hamster, an 3 intruder hamster, to that cage. And the male hamster who 4 lives there will immediately attack that intruder hamster and 5 try to drive him away. And what -- Professor Ferris has 6 actually done a couple of different kinds of studies. In some 7 work that has been published, he actually induced or increased 8 that aggression by giving a neurohormone called vasopressin, 9 and then he showed that fluoxetine would reduce that increased 10 amount of aggressive behavior. 11 Q. Let me get that straight. He's got these 12 hamsters who are territorially aggressive? 13 A. Yes. 14 Q. They like their turf, and if you get in it they 15 get after you? 16 A. Yes, sir. 17 Q. And he actually increased that territorial 18 aggression by giving them this stuff, vasopressin? 19 A. That's correct. 20 Q. And then he gave them Prozac, and he saw whether 21 it got better or worse? 22 A. The aggression was decreased. And he finds 23 exactly the same thing in hamsters that don't receive the 24 vasopressin; they still are aggressive, just less so, and that 25 aggression is also decreased when he gives Prozac. 178 1 Q. Now, again, for reasons of time, I don't want to 2 take you into all the detail of everything, but can you tell 3 us kind of how these scientists do these things? Like in this 4 hamster study, how does he measure aggression? 5 A. What he does is actually -- he actually 6 videotapes these hamsters in their cages. I have some of 7 those videotapes. I was watching one at home at one time and 8 my wife came in and was a little startled. 9 Q. We're not going to bring those in. 10 A. The point is that in the videotape they can go 11 back and review this and actually count and double-check their 12 observations. But the measurements involve how long does it 13 take for the hamster to attack the male intruder. During a 14 course of an observation time, how many attacks are there, how 15 many bites, how many different forms of aggressive behavior. 16 So he tabulates all of those for groups of hamsters treated 17 with vehicle and groups of hamsters treated with a drug such 18 as fluoxetine and he compares the effect of a drug to the 19 effect of placebo. 20 Q. It's kind of a placebo they give to some of 21 them? 22 A. Yes. 23 Q. I'll go to a new page here. By looking at your 24 notes, can you actually give us the numbers that he did here? 25 A. Well, in one such study, again, these are data 179 1 that we have measured extracellular serotonin concentrations 2 in these same animals, and at some point these particular data 3 will be published in a joint publication. But he measured how 4 long it took -- let's look at the -- well, he measured how 5 long it took for the hamster to bite the other hamster for the 6 first time. 7 Q. If you'll excuse me, Doctor, he gives it a kind 8 of fancy scientific name, latency to bite? 9 A. Latency to bite. It's how long it takes for the 10 first bite. 11 Q. The way I might say it is he's measuring in a 12 scientific way how fast it is these hamsters start attacking? 13 A. That's right. 14 Q. Okay. And what did he find? 15 A. In the control group, the number was rounded off 16 to 35 seconds; I believe these numbers are in seconds. And in 17 the Prozac group it was 231, so they were much slower in 18 beginning to aggress. And he counted the total number of 19 bites during the observation period, and in the control group 20 it was actually 9.9 on the average. 21 Q. Can we say ten? 22 A. Ten. And in the fluoxetine group it was 0.75, 23 so it was a very striking decrease. 24 Q. Zero -- 25 A. Zero point seven five. 180 1 Q. Can we round that off to one? 2 A. Okay. 3 Q. That's three quarters of one? 4 A. Yes. In other words, one-tenth -- less than 5 one-tenth the number of bites in the Prozac-treated hamsters. 6 Q. Okay. And so this is actually the way these 7 scientists go about measuring these kinds of aggressive -- 8 it's one of the ways they go about measuring aggression? 9 A. That's correct. 10 Q. All right. Let me turn now to another work. 11 There's some work been done by Raleigh and others; is that 12 right? 13 A. That's right. That's Doctor Michael Raleigh, 14 who is at UCLA. 15 Q. Okay. And what kind of animals did he use? 16 A. Doctor Raleigh and his co-workers study behavior 17 in monkeys, and they actually study monkeys living in troops 18 as they normally would live in the wild, and they have been 19 interested in the neurotransmitter serotonin in terms of its 20 effect on the behavior in these monkeys. And we supplied 21 fluoxetine to that group for their use in the studies in 22 monkeys, and they did a fairly complicated experiment, but I 23 think I can explain it. 24 Monkeys, if you've watched them on -- in the zoo 25 or on nature shows on TV, you know that they can behave I 181 1 think remarkably like some of us in terms of the different 2 kinds of behaviors that they show. They actually studied 3 monkeys in troops that were made up of three males, three or 4 more females, and whatever number of offspring of young 5 monkeys those monkeys had. And in a monkey troop like that, 6 one male monkey is always the dominant monkey, the leader of 7 the troop; he's the boss and everybody accepts that monkey as 8 their leader. The experiment that these investigators did was 9 to remove that dominant male monkey from the troop, and what 10 always happened after a period of a few weeks is that one of 11 the two remaining male monkeys became the dominant monkey. 12 The study they did was to treat one of those 13 male monkeys -- as soon as they removed the first dominant 14 male, they treated the two remaining males either with a drug 15 which would increase serotonin formation -- serotonin 16 function; they used fluoxetine in the study and they also used 17 tryptophan in the study, or they treated the monkeys with a 18 drug that would reduce serotonin function; they used two other 19 drugs to reduce serotonin function. And then they treated the 20 second male monkey with placebo. And they then observed which 21 male monkey became dominant over the period of the next few 22 weeks. 23 They did 12 experiments, and in every case, the 24 male monkey that was treated with fluoxetine or with 25 tryptophan became dominant over the other male monkey; 182 1 whereas, the male monkey that was treated with a drug that 2 reduced serotonin function became subordinate to the other 3 male monkey; that is, the placebo-treated monkey became 4 dominant. 5 Q. Wait a minute, Doctor. Doesn't that show that 6 the Prozac made the monkeys more aggressive because they 7 became more dominant? 8 A. No. No. No. That is not the case. 9 Q. Explain it to me. 10 A. These investigators actually measured -- I've 11 only told you one thing that they looked at, and that was the 12 dominance of the monkeys. In addition to that, they measured 13 a variety of other behaviors in these monkeys, including 14 aggressive behavior and including other kinds of positive 15 social behaviors. They have a system that is used in scoring 16 monkey behavior. They measured how much -- how many times a 17 monkey approached another monkey, how much time they spent 18 grooming other monkeys. That's one of common social 19 activities of monkeys; they will pick off fleas and lice and 20 other little things off of other monkeys. And they measured 21 how long a period of time the monkeys remained in close 22 contact with another monkey. 23 The point is, they measured what are considered 24 positive social interactions among those monkeys, and their 25 findings were that fluoxetine increased those positive social 183 1 interactions and it decreased the aggressive behavior in those 2 monkeys. The male monkey became dominant not by being 3 aggressive, but simply by being kinder to the other monkeys 4 and being liked better by the other monkeys. The monkeys more 5 or less elevated the monkey to that dominant position. The 6 monkey wasn't more aggressive. Fluoxetine and tryptophan 7 reduced the aggressive behavior. The monkeys became dominant 8 as a result of being better, kinder monkeys. 9 Q. I won't try and put that all up here, but, 10 basically, they tried to measure whether the monkeys that got 11 Prozac were more aggressive or less aggressive and found that 12 Prozac caused less aggression? 13 A. That's correct. 14 Q. And, kind of interesting, though maybe not 15 directly on point here, they actually found that the less 16 aggressive monkeys succeeded better in becoming leaders of the 17 troops? 18 A. That's correct. 19 Q. When was that work done, Doctor? 20 A. That work was -- that work was not published 21 until 1991. The work was done sometime before that. 22 Q. Okay. Let me turn to another subject -- I'm 23 sorry. I'm not paying attention to you and I should have. 24 When did you say it was done, sir? 25 A. The work was published in 1991, but it was done 184 1 sometime before that. 2 Q. All right. Now, Doctor, let me turn to a 3 slightly different subject here, and this is work that is 4 done, same thing, where Lilly gives the medicine to these 5 independent scientists, an independent scientist does work and 6 then reports back to you. But moving up the ladder from rats 7 to -- I don't know what the ladder is exactly -- to hamsters, 8 to monkeys, and turn to work done by Brown and Linnoila. Can 9 you tell us about that work? 10 A. Well, I think the publication that you're 11 referring to by Brown and Linnoila was fundamentally one of 12 the review articles that you mentioned in which they were 13 analyzing a number of publications that had appeared in the 14 literature from studies done by a variety of investigators, 15 and I'm not sure if any of those studies actually involved 16 Prozac or not. These were studies of the type that I referred 17 to earlier, in which cerebrospinal fluid levels of the 18 serotonin metabolite were measured. And this was reviewing a 19 number of studies which had reported what I said to you, that 20 in aggressive -- in patients who show aggressive, violent or 21 impulsive behavior, this finding of a decreased level of the 22 serotonin metabolite is one that has been made very 23 consistently in a number of different countries and a number 24 of different cultures was the point that they were making in 25 that paper. 185 1 Q. So these folks did this review article and they 2 looked at science done in lots of countries and lots of 3 different places? 4 A. That's correct. 5 Q. And I'm losing my number again. I hope it's 12. 6 And what's the fellow's name again, or woman? 7 A. Brown and Linnoila. 8 Q. And they reviewed this work which showed that in 9 humans -- what did it show again? 10 A. In humans who showed violent or aggressive or 11 impulsive behavior, there was a decrease in the serotonin 12 metabolite in the cerebrospinal fluid. 13 Q. And that's that 5-HIAA we heard about? 14 A. That's correct. 15 Q. That's down, and that shows that the serotonin 16 system -- 17 A. Function is down. 18 Q. All right. Now, again, I can't go through all 19 of this. Doctor Eichelman, did he do work in this area? 20 A. Doctor Eichelman is a psychiatrist who has been 21 interested in aggressive behavior, and he also wrote a review 22 article on the subject of what neurotransmitters influence 23 aggressive behavior. And one of the points that was made in 24 his paper is that there is a remarkable degree of agreement 25 between studies done in laboratory animals and studies done in 186 1 humans with regard to serotonin, indicating that a decreased 2 amount of serotonin is associated with increased aggression, 3 and larger amounts of serotonin function are associated with a 4 reduction in that aggression. 5 Q. So he indicated that the human and the animal 6 studies -- pardon my back; I can't do it any other way. He 7 indicated that they agreed? 8 A. Yes, sir. 9 Q. All right. We're almost through with this. 10 Doctor Spoont, is it? 11 A. Yes, sir. 12 Q. What did he do? 13 A. Well, I think he did about the same thing. He 14 reviewed what is known about serotonin and aggressive behavior 15 and reached about the same conclusion. 16 Q. All right. I'm going to just put "same thing." 17 And then we have some work done by Saudou and others. Can you 18 tell us about that, please? 19 A. Oh, you're referring to a paper that has been 20 only recently published and which I had called attention to 21 because it simply indicates that this connection between 22 serotonin and aggressive behavior continues to be supported by 23 new experimental data. This is a research group in France who 24 uses new techniques of molecular biology called genetic 25 engineering to produce a strain of mice which actually are 187 1 lacking in one particular type of serotonin receptor, a 2 receptor that is called the 5-HT1B receptor. 3 Q. Whoa. 5-HT1B? 4 A. The point really is that the only behavioral 5 abnormality in these mice was an increase in aggressive 6 behavior, which is just one more example of a decreased 7 serotonin function being associated with an increase in 8 aggressive behavior. 9 Q. These animals had different -- they were 10 genetically different and they were missing this? 11 A. They were missing one important part of the 12 serotonin system, that particular receptor. 13 Q. They were missing that because they had 14 different genetics than others? 15 A. That's correct. 16 Q. And the behavioral difference that you saw in 17 these animals was that they were more aggressive? 18 A. That's correct. 19 Q. Let me turn, I think, if I can find it -- let's 20 see; oh, maybe not -- to work by Doctor Charney and others. 21 Can you tell us what that showed? 22 A. Well, Doctor Charney and others at Yale -- this 23 is the same group of investigators that I mentioned before who 24 have done studies with this tryptophan-free drink. But in the 25 context of aggressive behavior, they also have examined the 188 1 literature and drawn attention to the fact that drugs which 2 increase serotonin function have been shown to decrease 3 aggressive behavior in a wide variety of animal models and 4 suggested that drugs of this sort ought to be useful in 5 treating aggressive, violent or impulsive behavior in humans, 6 and they were talking specifically about serotonin uptake 7 inhibitors such as Prozac. 8 Q. Okay. So that's Charney, and that's -- where 9 are they? 10 A. They are at Yale University School of Medicine. 11 Q. And that's what year? 12 A. That was -- that particular review article was 13 in 1990. 14 Q. And they again comment on the uniformity of the 15 work? 16 A. Yes, sir. 17 Q. How about Doctor Coccaro? Do we have some work 18 from him? 19 A. Yes. Professor Coccaro is at the University of 20 Pittsburgh at the Western Psychiatric Institute. 21 Q. And what did he do? 22 A. He continues -- he was actually on a television 23 show recently because of this work that he's doing, related to 24 a role of serotonin in aggressive behavior. And he has 25 done -- he is doing continuing studies with Prozac in the 189 1 treatment of patients with aggressive behavior. A preliminary 2 report of his work was -- it appeared back in 1990, in which 3 he had given fluoxetine to patients with impulsive-aggressive 4 behavior and found that there was in fact a decrease in their 5 aggressive behavior. 6 Q. Now, let me just slow down just a little bit 7 there. Here we're talking about human being patients who 8 suffer from psychiatric conditions by which -- in which they 9 become more impulsive and aggressive? 10 A. And more aggressive; that's correct. 11 Q. And what kind of conditions are those? 12 A. Well, I think these were patients with diagnosed 13 personality disorder. 14 Q. Okay. I'm going to write that one out. 15 Patients with personality disorder? 16 A. Yes, sir. 17 Q. Is personality disorder just what we might 18 describe of somebody we're unhappy with or is that a disease? 19 A. Well, it's a defined disease. I'm certainly not 20 a psychiatrist and I couldn't tell you in great detail about 21 the characteristics of this disease, but Doctor Coccaro is a 22 psychiatrist, and all I can tell you basically is that in 23 patients who he diagnosed with this condition who had 24 impulsive-aggressive, his findings were that fluoxetine 25 reduced their aggressive behavior. 190 1 Q. They were aggressive and they were impulsive? 2 A. Yes, sir. 3 Q. Is it fair to say -- I don't want to say it if 4 it isn't, but did Prozac help? 5 A. Yes, it did. In fact, on the television show 6 which was aired just about a month ago, they interviewed one 7 of the patients who had received Prozac. 8 Q. Doctor Cornelius, did he do some work, too? 9 We're coming to the end, I promise. 10 A. Yes. He also had studied patients with 11 borderline personality disorder and looked specifically at the 12 effect of fluoxetine on symptoms of impulsive and hostile or 13 aggressive behavior. 14 Q. All right. And what did he find? 15 A. He found that fluoxetine decreased those 16 symptoms. 17 Q. And these, of course, are patients, people, not 18 hamsters? 19 A. Yes. These are people. 20 Q. All right. A Doctor Fava, what did he do? 21 A. Doctor Fava and Doctor Rosenbaum are at Harvard 22 Medical School, and they have had a continuing interest in the 23 effect of fluoxetine on a condition which they describe as 24 anger attacks. An anger attack in their definition is an 25 inappropriate display of anger, and they find that these anger 191 1 attacks occurred fairly commonly among some depressed patients 2 that they treated, and they have published a couple of 3 different papers, a preliminary report and then a larger 4 study, in which Prozac reduced the occurrence of those anger 5 attacks in these depressed patients. 6 Q. Anger attacks. When was this work done or 7 published? 8 A. The most recent publication was in 1993. 9 Q. All right. 1993. And where were these 10 scientists? 11 A. They are psychiatrists at the Harvard Medical 12 School. 13 Q. And used Prozac. And what happened to the anger 14 attacks? 15 A. There was a decrease in the anger attacks. 16 Q. And they published more than one paper? 17 A. Yes, sir. They published one in 1991, and a 18 later one in 1993. 19 Q. Okay. I keep saying it, but I have one more. A 20 Doctor Markowitz. 21 A. Yes, sir. Doctor Markowitz is in Philadelphia, 22 I believe at Albert Einstein in Philadelphia, and he was 23 studying a group of patients who were mentally retarded who 24 showed aggressive behavior, particularly self-injurious 25 behavior, and he treated some of those patients with Prozac. 192 1 He treated 13 patients, and most of them became better. 2 Q. This is profoundly retarded. Does that have a 3 special meaning? 4 A. Well, it means pretty severely mentally 5 retarded. 6 Q. And they were exhibiting depression? 7 A. Yes. And, in particular, what he termed and 8 others termed self-injurious behavior. 9 A. Okay. And did Prozac seem to help? 10 A. Yes, it did. In most of the patients it helped. 11 Q. All right. Now, Doctor, having reviewed all of 12 that evidence for us -- by the way, is that all the evidence 13 there is? There's more? 14 A. Well, that's certainly, I think, the largest 15 amount of it and certainly representative of the available 16 information at this point. 17 Q. All right. Now, Doctor, as we sit here today 18 looking at all the evidence, not just what you brought here, 19 told us about today, but all the scientific evidence we have 20 about serotonin and Prozac and aggressiveness and violence, 21 does that evidence all point in one direction; does some of it 22 point one way, some of it the other way; is it mixed? Tell us 23 that, please. 24 A. I think it all points in one direction, and I 25 think that is exactly the point that several of these authors 193 1 have made previously in their review articles, that everything 2 seems to indicate that a decreased amount of serotonin may be 3 a cause of aggressive behavior and that drugs which increase 4 serotonin function have uniformly been found to decrease 5 aggressive behavior. 6 Q. Doctor, having reviewed all of that and in light 7 of your work you told us about earlier today, do you have an 8 opinion as to whether Prozac is an effective medicine, that it 9 works to help people sick with the disease of depression? 10 A. I certainly do have an opinion. 11 Q. And what is your opinion? 12 A. I believe it is a safe and effective medication 13 for treating depression. 14 Q. All right. Now, focusing on the safety part, 15 you believe it's safe in what sense? 16 A. I believe it is safe in the sense that it has 17 fewer side effects than the other antidepressant drugs that 18 are available. It's much safer in overdose than the other 19 antidepressant drugs are. 20 Q. Do you have an opinion as to whether or not 21 Prozac causes people to become suicidal, aggressive or 22 violent? 23 A. I do have an opinion. 24 Q. And what is your opinion, sir? 25 A. My opinion is that it does not cause those 194 1 effects. 2 Q. Your Honor, I would offer the Witness for 3 cross-examination by Mr. Smith with one thing, if I might come 4 to sidebar for one minute, first. 5 (BENCH DISCUSSION) 6 MR. McGOLDRICK: Judge, there is one set of data 7 which I don't believe I was able to offer under Your Honor's 8 rulings. It's relatively -- it's not as big as the bulk which 9 I just put in, and all I'd like to do before I turn the 10 Witness over is have some time at Your Honor's discretion to 11 do an avowal. 12 JUDGE POTTER: Okay. We'll do it on a break. 13 (BENCH DISCUSSION CONCLUDED) 14 JUDGE POTTER: Mr. Smith, are you going to be 15 awhile? 16 MR. SMITH: Yes, Your Honor. 17 JUDGE POTTER: Maybe it would make sense to go 18 ahead and recess today and let you start fresh in the morning. 19 MR. SMITH: Well, I can go for -- you know, it's 20 not me that's dragging this case into mid December, Your 21 Honor. I'm willing to work for 30 minutes. 22 JUDGE POTTER: My only thing is that sometimes I 23 find with lawyers if they take 20 minutes and then stop, they 24 tend to repeat the 20 minutes in the morning. 25 MR. SMITH: I won't repeat it. 195 1 JUDGE POTTER: Okay. Mr. Smith. 2 MR. SMITH: Was that the jury groaning? If 3 that's the jury groaning I'm not going to ask any questions 4 today, Your Honor. 5 No. Seriously, if everybody's tired I can wait. 6 That's fine. 7 UNIDENTIFIED JUROR: It's been a long day. 8 MR. SMITH: It's been a lot of -- 9 JUDGE POTTER: All right. Okay. 10 Ladies and gentlemen, let me ask you one other 11 thing. If I could, I'd like to quit at 4:30 tomorrow. Have 12 you-all -- would it cause you-all any problem to come in at 13 8:30? I don't know about your bus schedules or what other 14 commitments. Is there anybody that would cause a problem? I 15 tell you what, rather than confuse everybody, we'll just stick 16 with 9:00 and give up a half hour tomorrow. Okay. 17 I give you the same admonition I've given you 18 before. Do not permit anybody to speak to or communicate with 19 you on any topic connected with this trial, including your 20 friends, the media, whatever. Do not discuss it among 21 yourselves or form or express opinions about it. We'll stand 22 in recess till 9:00 tomorrow morning. 23 (JURORS EXCUSED AT 4:30 P.M.; AVOWAL 24 TESTIMONY BEGINS BY MR. McGOLDRICK) 25 Q. Doctor Fuller, there were some articles and some 196 1 science which -- and I'm not sure, I hope I can get it 2 straight now -- which were not before September of 1989 and 3 were not where Lilly gave the medicine to the researcher which 4 I didn't ask you about. Can you dig those out? I may be able 5 to help you here. I tried to keep them separate but I'm not 6 sure I succeeded. If I didn't, I may have to do it quickly in 7 the morning, but... I know one, the sable foxes. 8 A. Yes. That may be the only one. 9 Q. Okay. That's Popova, et al? 10 A. Yes, sir. 11 MR. McGOLDRICK: Your Honor, you want me to just 12 go ahead on through that? 13 JUDGE POTTER: Whatever you were going to ask 14 him if you'd been able to run free. 15 Q. I have that if you'd like to look at mine. 16 A. I have it. 17 Q. Now, Doctor Fuller, was there work done by 18 Doctor Popova and others which also dealt with the question of 19 serotonin and violence or aggressive behavior? 20 A. Yes. 21 Q. And when was that done? 22 A. The work was published in 1991. 23 Q. And did Lilly provide any medicines or anything 24 like that to Popova? 25 A. Well, not for the purpose of this study. I 197 1 happen to know Doctor Popova; it's a lady named Nina Popova, 2 and I think we may have supplied fluoxetine to her for other 3 studies, but this particular study doesn't involve that 4 fluoxetine, no. 5 Q. All right. Well, that fits in a category that 6 we weren't supposed to go into here before the jury, and I 7 want to ask you about it now. My question to you is, what did 8 Doctor Nina Popova do that is relative to aggression and 9 serotonin? 10 A. Well, she described a study which I thought was 11 noteworthy partly because it was still an additional animal 12 species other than we have mentioned before in that it was in 13 silver foxes, which are not something that are commonly 14 studied in laboratories but which were being bred in captivity 15 in Russia. And the purpose, I believe, although it wasn't 16 stated in this article, was to provide fur coats and fur hats. 17 It happens that when these silver foxes are bred in captivity, 18 some of them become tame and nonaggressive, but others of them 19 remain very aggressive and will bite the handlers if given a 20 chance. And what Doctor Popova did was to analyze in various 21 brain regions of those silver foxes the concentration of 22 serotonin. 23 And the finding was that those silver foxes 24 which were aggressive tended to have lower amounts of 25 serotonin than did those silver foxes which were 198 1 nonaggressive. And her interpretation was that the increased 2 amount of serotonin function may have been the cause of that 3 decreased amount of aggressive behavior, which is simply a 4 nondrug study that is completely consistent with all of the 5 drug studies that I talked about that have been done in other 6 kinds of animal species. 7 Q. Just very briefly, some of the silver foxes, 8 they breed them in captivity probably because the Russians 9 wear a lot of fur coats? 10 A. Yes, sir. 11 Q. And these foxes, some of them in captivity get 12 less aggressive and some of them get more aggressive? 13 A. Some of them remain aggressive, I would say, 14 yes. 15 Q. Wild foxes are pretty aggressive to start with? 16 A. I think so. 17 Q. And they measured this serotonin function or 18 marker, 5-HIAA? 19 A. They measured actually serotonin itself and also 20 the metabolite 5-HIAA. 21 Q. And they found a difference between the 22 aggressive ones and the nonaggressive ones? 23 A. That's correct. 24 Q. And the difference was? 25 A. The aggressive ones had less serotonin. 199 1 Q. And that suggests that reduced serotonin is 2 associated with aggression, and elevated or normal is 3 associated with nonaggression? 4 A. That's correct. 5 MR. McGOLDRICK: I think that's all I have, 6 Judge. If Mr. Smith would be so kind, I might have missed one 7 other; I don't think I did. If I did, I might ask the -- 8 MR. SMITH: Sure. You want to put it in later? 9 JUDGE POTTER: Okay. And the reason we're 10 stopping at 4:30 tomorrow is one of the jurors, one of his 11 children has a problem. 12 SHERIFF CECIL: Her baby-sitter is her mother, 13 and she's being operated on. 14 JUDGE POTTER: There's some confusion with a 15 juror, so that's why we're quitting at 4:30. 16 MR. SMITH: Can I ask one other thing, Your 17 Honor? It's my understanding that after Doctor Fuller, Doctor 18 Wernicke is going to be on; is that correct still? 19 MR. FREEMAN: Yes. 20 MR. McGOLDRICK: Yes. 21 MR. SMITH: I don't know. Do you think that 22 you'll be -- if I take, say, an hour, hour and a half with 23 Doctor Fuller in the morning, you might have some redirect? 24 We're going to quit at 4:30. Do you think you're going to be 25 taking the bulk of the day with Doctor Wernicke? I'm just 200 1 wondering whether to sleep at all or just a couple hours. 2 MR. McGOLDRICK: I'll give you my best estimate. 3 I believe, it is my plan that I will be turning Doctor 4 Wernicke over to you for cross and will be doing so probably 5 by early afternoon, if not sooner. And I might -- it might be 6 midafternoon. And I was longer this afternoon than I thought 7 I was going to be. 8 JUDGE POTTER: If Doctor Wernicke comes your way 9 tomorrow, it won't be a surprise. 10 MR. McGOLDRICK: I really do think that. 11 Judge, I'm sorry. One other thing. I can do it 12 tomorrow, if you'd like. At some point I'd like to offer 13 those boards that I used in evidence. If you'd like to do 14 that in the presence of the jury, I can. 15 JUDGE POTTER: Is there any problem with the 16 pictures, Mr. Smith? 17 MR. McGOLDRICK: Offering those in evidence, the 18 boards? 19 MS. ZETTLER: Can we get smaller copies of 20 those? 21 MR. McGOLDRICK: I do have a photograph, a 22 smaller photograph. 23 MS. ZETTLER: If we can get smaller copies in. 24 Okay. 25 JUDGE POTTER: Have you marked them, Mr. Myers? 201 1 MR. MYERS: Yes, sir. 2 JUDGE POTTER: 180-A, as in alpha, through E as 3 in echo, are admitted into evidence. 4 (PROCEEDINGS TERMINATED THIS DATE AT 4:35 P.M.) 5 * * * 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 202 1 STATE OF KENTUCKY )( )( Sct. 2 COUNTY OF JEFFERSON )( 3 I, JULIA K. McBRIDE, Notary Public, State of 4 Kentucky at Large, hereby certify that the foregoing 5 Transcript of the Proceedings was taken at the time and place 6 stated in the caption; that the appearances were as set forth 7 in the caption; that prior to giving testimony the witnesses 8 were first duly sworn; that said testimony was taken down by 9 me in stenographic notes and thereafter reduced under my 10 supervision to the foregoing typewritten pages and that said 11 typewritten transcript is a true, accurate and complete record 12 of my stenographic notes so taken. 13 I further certify that I am not related by blood 14 or marriage to any of the parties hereto and that I have no 15 interest in the outcome of captioned case. 16 My commission as Notary Public expires 17 December 21, 1996. 18 Given under my hand this the__________day of 19 ______________________, 1994, at Louisville, Kentucky. 20 21 22 23 24 _____________________________ 25 NOTARY PUBLIC 203 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25