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.