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 MONDAY, OCTOBER 10, 1994 15 VOLUME XI 16 17 * * * 18 19 20 _____________________________________________________________ 21 REPORTER: JULIA K. McBRIDE Coulter, Shay, McBride & Rice 22 1221 Starks Building 455 South Fourth Avenue 23 Louisville, Kentucky 40202 (502) 582-1627 24 FAX: (502) 587-6299 25 2 1 2 I_N_D_E_X _ _ _ _ _ 3 Bench Discussion......................................... 4 4 WITNESS: DOCTOR_RAY_FULLER - By Deposition _______ ______ ___ ______ 5 Examination by Mr. Smith................................. 11 6 WITNESS: DOCTOR_IRWIN_SLATER - By Deposition _______ ______ _____ ______ 7 Examination by Mr. Smith.................................185 8 Hearing in Chambers......................................247 9 Reporter's Certificate...................................255 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 4 FOR THE PLAINTIFFS: 5 PAUL L. SMITH Suite 745 6 Campbell Center II 8150 North Central Expressway 7 Dallas, Texas 75206 8 NANCY ZETTLER 1405 West Norwell Lane 9 Schaumburg, Illinois 60193 10 IRVIN D. FOLEY Rubin, Hays & Foley 11 300 South, First Trust Centre Louisville, Kentucky 40202 12 13 FOR THE DEFENDANT: 14 EDWARD H. STOPHER Boehl, Stopher & Graves 15 2300 Providian Center Louisville, Kentucky 40202 16 LAWRENCE J. MYERS 17 Freeman & Hawkins 4000 One Peachtree Center 18 303 Peachtree Street, N.E. Atlanta, Georgia 30308 19 20 ALSO PRESENT: 21 DR. W. LEIGH THOMPSON 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 Monday, October 10, 1994, at approximately 9:35 A.M., said 5 proceedings occurred as follows: 6 7 * * * 8 (THE FOLLOWING PROCEEDINGS OCCURRED IN COURT OUT 9 OF THE PRESENCE OF THE JURY) 10 MR. MYERS: We've reached an agreement, Judge, 11 on everything that's on the Fuller objections except for three 12 items, and those relate to Pages 115, 225 and 248. 13 MS. ZETTLER: Right. 14 MR. MYERS: Otherwise, we've agreed on them. 15 JUDGE POTTER: All right. Tell me who Mr. 16 Fuller is. 17 MR. MYERS: Doctor Fuller is an employee of 18 Lilly. He was a basic neuroscientist that was one of the 19 people involved in the early development of the drug. 20 MS. ZETTLER: He will be here live during 21 Lilly's portion of the case. 22 JUDGE POTTER: He will be here live during your 23 portion of the case? 24 MR. MYERS: Yes, sir. 25 MS. ZETTLER: We're using him basically as an 5 1 educational witness, Judge, to set the predicate on the 2 serotonin system, et cetera. 3 JUDGE POTTER: Okay. 115. 4 MS. ZETTLER: We've designated the first two, he 5 wants the rest of the page. 6 JUDGE POTTER: I was just reading that to get 7 the flow of where we are. 8 MR. MYERS: Yeah. Because it runs into it. 9 JUDGE POTTER: (Reviews documents). 10 MS. ZETTLER: Our problem with it, Judge, is 11 that it just gets confusing. 12 JUDGE POTTER: That's my problem. 13 MS. ZETTLER: It basically is an ecology on 14 terminology, semantic and it just gets confusing, and if there 15 was anything they really want him to explain, they're going to 16 have him live to explain it. 17 MR. MYERS: Your Honor, our position is that it 18 is a continuation from the question earlier asked and that's 19 why we'd like it read. 20 MS. ZETTLER: This stuff is going to be tough 21 enough for the jury to understand. 22 JUDGE POTTER: I'm going to agree with them on 23 that, that it's tough enough as it is. Objection is 24 overruled. 25 MS. ZETTLER: Okay. Next one is 225, Judge. 6 1 And it's the same type of thing. We think it's confusing; 2 it's just a semantics type of thing. 3 JUDGE POTTER: I take it there's going to be 4 some squabbling about the term down regulation? 5 MR. MYERS: I don't know that there's going to 6 be any squabbling, but I think the entire discussion preceding 7 and following that question is on the subject, and I think 8 that if they're going to read it they should be required to at 9 least read that portion where he voices his disagreement with 10 the terminology. 11 MS. ZETTLER: The problem is, is that the 12 disagreement with the terminology that other people outside 13 this case are using, okay, not the terminology as used in this 14 question and this is just going to get confusing again. 15 You're looking at an exhibit and the exhibit uses this 16 phraseology; this is not the phraseology that we're using, and 17 all he's saying here is that he disagrees with the phraseology 18 that's used in the exhibit and that's not really an issue. 19 MR. MYERS: If you put the exhibit in, they're 20 entitled to question about that. 21 JUDGE POTTER: Okay. I'm going to sustain that 22 objection. 248, you want that turned out? 23 MS. ZETTLER: Yeah. Because I want to fix our 24 other copies. I'm missing 248. Maybe it's out of sequence. 25 MR. MYERS: That's 347. I'm in the three 7 1 hundreds and I shouldn't be. 2 JUDGE POTTER: (Reviews document). I knew the 3 answer to that one. You can't see the neuron with a naked 4 eye, heavy-duty science here. You can see it with a 5 microscope? Neuron? Oh, neuron is the thrill doodad. 6 MS. ZETTLER: Judge, that's just where I got 7 that term wrong. 8 JUDGE POTTER: Putative is the word they want 9 here; right? 10 MS. ZETTLER: No, sir. That was from another 11 deposition. 12 JUDGE POTTER: Let me finish reading. 13 MS. ZETTLER: Okay. I'm sorry. 14 JUDGE POTTER: Has the word -- how do you 15 pronounce it? 16 MS. ZETTLER: Putative. 17 MR. MYERS: Putative. 18 JUDGE POTTER: Has the word putative appeared 19 before anywhere? 20 MR. MYERS: Not in this deposition. In Doctor 21 Stark's and Doctor Slater's deposition there will be. 22 MS. ZETTLER: It's used correctly in those other 23 depositions, Judge, it's not used correctly here and that's 24 the part that just gets confusing. 25 MR. MYERS: Our position is I don't have any 8 1 problem with the portions being read in the other deposition, 2 but if they're going to be read I think it should be read 3 here. 4 JUDGE POTTER: They want to use that word. Oh, 5 it is 18 through 24 and 1 through 2, so that is sustained. I 6 thought you were trying to get in the... 7 MR. MYERS: Okay. That's it. 8 MR. SMITH: Judge, I have another objection, and 9 I think it's going to be confusing to the jury. I put my suit 10 on I know this morning before Mr. Myers did and I'd like for 11 him to go home and change, please. 12 JUDGE POTTER: But you have different ties. 13 MR. MYERS: Mr. Freeman is attending a funeral 14 in Atlanta today so he won't be here today. 15 (THE FOLLOWING PROCEEDINGS OCCURRED IN 16 OPEN COURT) 17 SHERIFF CECIL: The jury is now entering. All 18 jurors present. Court is now in session. 19 JUDGE POTTER: Please be seated. 20 Mr. Smith, do you want to call your next 21 witness. 22 MR. SMITH: Yes, Your Honor. At this time we 23 would offer portions of the deposition of Doctor Ray W. 24 Fuller. 25 JUDGE POTTER: Okay. Ladies and gentlemen, let 9 1 me go over something with you. Mr. Smith is calling Doctor 2 Fuller by deposition. You're going to hear me say this basic 3 thing to you again and again, and -- it's kind of like the 4 admonition, which reminds me, Ms. Franklin, did you have any 5 trouble with the admonition this weekend? 6 JUROR FRANKLIN: No, sir. 7 JUDGE POTTER: And I take it no one else had any 8 problems? I'll say it over and over to you, and the reason 9 I'll say it over and over to you is because it's something 10 that people have the tendency to forget, but it's important. 11 A deposition is sworn testimony taken outside the courtroom 12 prior to trial. Both sides have an opportunity to be there 13 and examine and cross-examine the witness, just the way they 14 do here at trial. The witness is placed under oath. One side 15 asks questions and then the other side asks questions. A 16 record of those questions and answers can be made in one of 17 two ways or even both ways. There can be a Court Reporter 18 just as there is here who takes down every word and every 19 answer and then it's typed up and you have a written 20 transcript of the questions and answers. Sometimes the 21 process is videotaped. Under certain circumstances, the 22 videotape can be played for you, or, if there's a transcript, 23 the questions and answers can be read to you. When this 24 happens, you will treat the evidence exactly as you would as 25 if the witness were here live. Okay. And, obviously, the 10 1 witness is not here live so there's some loss of what the 2 witness looks like and their voice and whatnot, but as far as 3 what they say, you give it the same treatment you would as if 4 the witness were here testifying live. In other words, it's 5 not some kind of second-class evidence or it doesn't count as 6 much because it's a deposition as opposed to a live witness. 7 It's much more difficult to follow. Not so much the televised 8 part because I think we've gotten ourselves trained to where 9 we can look at TV screens a pretty long time, but it's 10 sometimes hard to follow when it's being read to you. But I 11 emphasize it is sworn testimony, it's taken outside the 12 courtroom prior to trial, and it will be given the same weight 13 you would as if the witness were here testifying live. Mr. 14 Smith? 15 MR. SMITH: Your Honor, at this time we request 16 that Ms. Zettler be allowed to read the response. 17 JUDGE POTTER: Okay. 18 MS. ZETTLER: Is it okay if I sit up here, 19 Judge? 20 JUDGE POTTER: Yeah. That's the way... 21 MR. SMITH: Beginning on Page 8, this is the 22 deposition of Doctor Ray W. Fuller, taken at the office of 23 Baker and Daniels, 300 North Meridian Street, Suite 2700, 24 Indianapolis, Indiana 46204, on April 14th and 15th, 1994; 25 said deposition taken pursuant to Notice in accordance with 11 1 the Rules of Civil Procedure. 2 Beginning at Page 11, Line 19. 3 (MR. SMITH & MS. ZETTLER READ THE FOLLIWNG 4 TESTIMONY FROM DOCTOR FULLER'S DEPOSITION) 5 Q. Would you please state your name, sir? 6 A. My name is Ray Fuller. 7 Q. Do you have a middle name, Doctor Fuller? 8 A. Yes, I do. 9 Q. Can I have it, please? 10 A. It's Ward, W-A-R-D. 11 Q. How old a man are you, sir? 12 A. Let's see. I'm 58. 13 Q. And your residence address, please? 14 A. 1008 Hudson Bay Drive, Greenwood, Indiana. 15 Q. And is Greenwood close to Indianapolis, Indiana? 16 A. Yes, it is. 17 Q. How close is it? 18 A. I think it borders. 19 Q. Is it a suburb of Indianapolis? 20 A. Yes. 21 Q. How are you employed, sir? 22 A. I'm employed at Eli Lilly and Company. 23 Q. And what is your present position with Eli Lilly 24 and Company? 25 A. My title is Lilly Research Fellow. 12 1 Q. Are you employed by the Eli Lilly Laboratories 2 or Eli Lilly and Company, Inc.? 3 A. I'm part of Lilly Research Laboratories. 4 Q. Who currently is president of Lilly Research 5 Laboratories? 6 A. August Watanabe. 7 Q. And then under him are there vice-presidents? 8 A. Yes. 9 Q. Do you report directly to one of the 10 vice-presidents, Doctor Fuller? 11 A. Yes, I do. 12 Q. Which vice-president do you report to? 13 A. Stephen Paul. 14 Q. Paul? 15 A. Yes. 16 Q. And what is Stephen Paul's position? 17 A. Vice-president of Lilly Research Laboratories. 18 Q. Does he have a particular division or particular 19 area of responsibilities? 20 A. Yes. 21 Q. What is that, please, sir? 22 A. It's central nervous system, gastrointestinal 23 and genitourinary research or something like that. 24 Q. Is Stephen Paul a medical doctor? 25 A. Yes, he is. 13 1 Q. And do you know if Doctor Paul has a specialty? 2 A. He's a psychiatrist. 3 Q. And do you report directly to Doctor Paul as a 4 Lilly Research Fellow? 5 A. That's right. 6 Q. How many Lilly Research Fellows are there in 7 Lilly research labs? 8 A. I don't know the answer. 9 Q. Are there more than one Lilly Research Fellows 10 in the CNS division? 11 A. No. 12 Q. How many Lilly research advisers are there 13 currently in the CNS division such as Doctor Wong? 14 A. I'm not sure I know the answer. Maybe three. 15 Q. Who would be other Lilly research advisers in 16 addition to Doctor Wong in the CNS division? 17 MS. ZETTLER: I don't think that was supposed to 18 be read, Paul. I don't have the next page. 19 MR. SMITH: Let's begin on Page 23, Line 11. Is 20 that where you are? 21 MS. ZETTLER: Yes. 22 Q. How long have you been a Lilly Research Fellow? 23 A. I believe since 1989. 24 Q. As a Lilly Research Fellow, are you an officer 25 of Lilly Research Labs? 14 1 A. No. 2 Q. Is the position Lilly Research Fellow something 3 that is given based on any particular distinction? 4 A. What do you mean by distinction? 5 Q. Number of years in service, number of articles 6 published, a particular research milestone or something of 7 that nature? 8 A. No, nothing in particular of that nature. 9 Q. Who are the individuals who are able at Lilly to 10 confer the position of Lilly Research Fellow on any particular 11 scientist? 12 A. I think it would be Doctor Watanabe and his 13 staff. 14 Q. On a vice-presidential level, I would assume? 15 A. I think that's correct. 16 Q. Has Doctor Watanabe been the president of Lilly 17 Research Labs ever since you've been a Lilly Research Fellow? 18 A. No. He's only been president for the last four 19 months, I believe. 20 Q. Who was the president of Lilly Research Labs 21 prior to Doctor Watanabe? 22 A. Doctor Mel Perelman. 23 Q. It's my recollection that Doctor Perelman is by 24 training an internist? 25 A. No, that's not correct. 15 1 Q. What is his specialty? 2 A. He's a chemist. 3 Q. Doctor Perelman is not a medical doctor? 4 A. That's correct. 5 Q. Was Doctor Perelman the president of Lilly 6 Research Labs when you became a Lilly Research Fellow? 7 A. Yes, he was. 8 Q. And what position was Doctor Paul? 9 A. Doctor Paul was not a Lilly employee; he was 10 Director of the National Institute of Mental Health at that 11 time, I believe. 12 Q. When did Doctor Paul leave his position as the 13 director of the National Institute of Mental Health to become 14 the vice-president of Lilly Research Labs? 15 A. It would have been less than two years ago. 16 Q. Were you involved in the decision to hire Doctor 17 Paul from the National Institute of Mental Health? 18 A. Maybe you should explain what you mean by 19 "involved." 20 Q. Were you part of a committee or group of 21 individuals who assisted in the selection of Doctor Paul as 22 the new vice-president in charge of the CNS division at Lilly 23 Research Labs? 24 A. I certainly talked with him and that sort of 25 thing. As far as being part of the group that ultimately made 16 1 the decision to hire him, I would say no, I was not. 2 Q. Were you part of a search committee or anything 3 of that nature? 4 A. No, I was not. 5 Q. But you had known Doctor Paul for some time 6 prior to him coming with Lilly, had you not? 7 A. Yes. Uh-huh. 8 Q. How long have you known Doctor Paul? 9 A. I don't remember exactly. Possibly ten or more 10 years. 11 Q. How did you come to know Doctor Paul? 12 A. I don't know -- I don't remember exactly how we 13 first met. We knew each other from scientific meetings and 14 that sort of thing. 15 Q. Was Doctor Paul with the National Institute of 16 Mental Health for the entire time that you knew him up until 17 the time that he joined Lilly? 18 A. It's possible I met him before he went to the 19 National Institute of Mental Health, but probably he was there 20 at the time I met him. 21 Q. Do you recall where Doctor Paul was prior to him 22 being with the National Institute of Mental Health? 23 A. He was at the University of Chicago at one time. 24 I'm not sure if that was immediately prior to NIMH. 25 Q. Do you have a staff of individuals who work 17 1 under you? 2 A. Yes, I do. 3 Q. Who are they? 4 A. There are two individuals. One is Ken Perry and 5 one is Susan Luecke, L-U-E-C-K-E. 6 Q. And what do Mr. Perry and Ms. Luecke do? 7 A. They do laboratory experiments in animals. 8 Q. What is their title, laboratory assistants, 9 laboratory technicians? 10 A. It's something like associate biochemist. We 11 have a system of titles that I frankly don't remember the 12 particular one for them since I don't use it. 13 Q. And those systems and titles change from time to 14 time, don't they? 15 A. That's correct. 16 Q. Are you currently involved in research? 17 A. Yes. 18 Q. Does your research currently involve fluoxetine 19 hydrochloride? 20 A. It does not principally involve fluoxetine 21 hydrochloride. We may from time to time do animal 22 experiments. We do from time to time do animal experiments 23 with fluoxetine. 24 Q. What was the last animal experiment that you did 25 employing fluoxetine? 18 1 A. I don't know for sure that I can remember the 2 very last one. A recent one was a series of experiments 3 measuring extracellular serotonin in the rat brain after 4 administration of fluoxetine. 5 Q. And were you studying fluoxetine and the effects 6 of fluoxetine in that experiment? 7 A. Yes. 8 Q. And this was an experiment to investigate 9 another specific compound that was under investigation by 10 Lilly? 11 A. No, it was not. 12 Q. What were the results of that experiment, Doctor 13 Fuller? 14 A. Well, there were a series of experiments, and 15 they showed that fluoxetine increased the concentration of 16 serotonin in extracellular fluid in different regions of the 17 rat brain and that it acted synergistically with 18 L5-hydroxytryptophan and that the increase was dependent upon 19 neurotransmitter release and particularly release from 20 serotonin neurons. 21 Q. How long did that experiment last? Was it a 22 series of experiments? 23 A. A series of experiments would have lasted over 24 a period of one to two years. 25 Q. This was not the first experiment you had done 19 1 in connection with examining extracellular levels of serotonin 2 in rat brains, was it? 3 A. We began experiments like that more than two 4 years ago. 5 Q. You were doing experiments, investigating 6 amounts of extracellular serotonin in rat brains back in the 7 '70s, were you not? 8 A. No, we were not. 9 Q. You were measuring quantities or levels of 10 serotonin of rat brains back in the '70s, were you not? 11 A. Yes. That is right. 12 Q. What is new or distinct about this latest 13 project or experiment that you had done? 14 A. The series of experiments that I mentioned as 15 having been done recently used the technique of brain 16 microdialysis, which was not available back in the '70s. 17 Q. Is that similar to kidney dialysis? 18 A. It is similar only to the extent that the type 19 of microdialysis fiber used is the same. 20 Q. Have you published the results of that 21 experiment yet? 22 A. We have published results from those 23 experiments, yes. 24 Q. When and where? 25 A. We published one paper in Life Sciences and one 20 1 paper in the Journal of Pharmacy and Pharmacology, and those 2 would have been 1992 and 1993, I think. 3 Q. So you're still active, Doctor Fuller, I would 4 assume, in research in connection with fluoxetine and 5 serotonin and CNS compounds; is that correct? 6 A. Yes. That's correct. 7 Q. As a Lilly Research Fellow, are you free to 8 pursue your research as you see fit, within the bounds of 9 reason, of course? 10 A. Yes. 11 Q. In other words, I guess what I'm asking you is, 12 Doctor Paul doesn't come to you and say, "Doctor Fuller, I 13 want you to run a particular experiment for me and I want you 14 to set it up in a particular manner." 15 A. That's correct, he does not. 16 Q. Your research ideas are your ideas based on 17 your knowledge, experience and training; is that correct? 18 A. And things I learned from other people, yes. 19 Q. Are you a member of any particular project team 20 at this time? 21 A. No. 22 Q. You were at one time the fluoxetine project 23 team leader, as I understand it? 24 A. That is correct. 25 Q. When were you last a member of the fluoxetine 21 1 project team? 2 A. Whenever -- could you read that one again? 3 Q. Go ahead, read the answer. 4 A. Whenever it was disbanded, and I don't remember 5 what year that was. 6 Q. Give me an approximate date, please. 7 A. It would have been, I suppose, five years ago. 8 Q. Was it after fluoxetine had been approved -- 9 A. Yes. 10 Q. -- as Prozac for marketing to human beings in 11 the United States? 12 A. Yes, it was after that, I believe. 13 Q. How long afterwards? Shortly afterwards? 14 A. Probably within two years afterwards. 15 Q. We'll come back and talk about this latest 16 research that you've done later. What I would like to do, 17 Doctor Fuller, and I don't know want to take up too much time 18 doing this, but I would like to get a brief chronology of your 19 various activities within Eli Lilly and Company, and I guess 20 it might be just as easy to work back. You've been a Lilly 21 Research Fellow since 1989; is that correct? 22 A. If I remember correctly, that is. 23 Q. Prior to being a Lilly Research Fellow, what was 24 your position with Eli Lilly and Company? 25 A. Research adviser. 22 1 Q. And can you give me the dates that you would 2 held the title, Research Adviser? 3 A. It would have been between 1976 to 1989. 4 Q. Prior to your being named a research fellow, 5 were there any individuals in the CNS division who had ever 6 been research fellows? 7 A. I don't remember for sure how long the CNS 8 division has existed as a CNS division. I think the answer is 9 no. 10 Q. When I say CNS division I'm talking about that 11 group of scientists, physicians and researchers who worked on 12 drugs or compounds that would be used in connection with the 13 brain or nervous system, whether it be called CNS division or 14 some other title. Do you follow what I'm saying? 15 A. Yes, I do. 16 Q. Prior to becoming research adviser in 1976, what 17 was your job title? 18 A. It was research associate. 19 Q. And for what years did you hold that title? 20 A. 1971 to 1975. 21 Q. During that period of time, was there a research 22 adviser to whom you reported? 23 A. No. 24 Q. And before you became a research adviser with 25 Lilly, what job title did you hold? 23 1 A. Head of the department of metabolic research. 2 Q. And how long did you hold that position? 3 A. 1968 to 1971. 4 Q. Prior to being head of the department of 5 metabolic research what was your job title? 6 A. Research scientist. 7 Q. And to whom -- what period of time did you -- 8 A. 1967 to 1968. 9 Q. And to whom did you report at that time? 10 A. Irwin Slater. 11 Q. And before Research Scientist what was your 12 position? 13 A. Senior pharmacologist. 14 Q. And for what years did you hold that position? 15 A. 1963 to 1967. 16 Q. And to whom did you report at that level? 17 A. Irwin Slater. 18 Q. You started with Lilly in 1963? 19 A. That's right. 20 Q. Are you a pharmacologist, Doctor Fuller? 21 A. Yes. 22 Q. And where did you get your pharmacologist 23 training? 24 A. My academic training was not in pharmacology. 25 Q. Before you joined Lilly in 1963, were you 24 1 working on a full-time basis? 2 A. Yes, I was. 3 Q. Where? 4 A. At the Fort Wayne State Hospital. 5 Q. In what capacity? 6 A. I was director of the research laboratory. 7 Q. And for what years were you at Fort Wayne State 8 University? 9 A. 1961 to 1963. 10 Q. And prior to 1961, or immediately before you 11 went with Fort Wayne State, you were a student; is that 12 correct? 13 A. That is right. 14 Q. Tell us then, Doctor Fuller, the extent of your 15 education starting with high school. Where did you go to high 16 school and when did you graduate from high school? 17 A. I went to high school at Anna Jonesborough 18 Community High School in Illinois. 19 Q. When did you graduate from high school? 20 A. 1952. 21 Q. After high school? 22 A. Attended Southern Illinois University. 23 Q. Did you graduate from Southern Illinois 24 University? 25 A. Yes. 25 1 Q. In what year? 2 A. Bachelor's Degree in 1957. 3 Q. Bachelor of Science? 4 A. Bachelor of Arts, actually. 5 Q. What was your major in college? 6 A. Chemistry. 7 Q. You majored in chemistry, but you received a -- 8 the degree you received was a Bachelor of Arts? 9 A. That's correct. 10 Q. Why was that? 11 A. I was in the College of Liberal Arts and 12 Sciences; the Bachelor of Arts Degree meant that I had a 13 foreign language proficiency, as well as a science degree or 14 training. 15 Q. Then I assume you did postgraduate training 16 after you were graduated from Southern Illinois University? 17 A. Yes. 18 Q. Where did you get your postgraduate training? 19 A. I began it at Southern Illinois University. 20 Q. In what discipline? 21 A. Microbiology. 22 Q. And did you complete a degree at Southern 23 Illinois University postgraduate? 24 A. Yes. 25 Q. What degree did you receive there? 26 1 A. Master of Arts. 2 Q. Were you taking some foreign language in the 3 graduate program also that would -- 4 A. I passed a proficiency exam. 5 Q. Then after -- when did you get your Master's 6 Degree? 7 A. 1958. 8 Q. And then after you graduated from Southern 9 Illinois University did you do further training? 10 A. Yes. 11 Q. Where? 12 A. Purdue University. 13 Q. And you received a Ph.D. from Purdue? 14 A. That's right. 15 Q. In what year? 16 A. 1961. 17 Q. And in what discipline? 18 A. Biochemistry. 19 Q. Did you teach at Southern Illinois University? 20 A. A little bit. 21 Q. Did you teach at Purdue? 22 A. A little bit. 23 Q. Were you employed part time while you were 24 either working on your Master's or your Ph.D.? 25 A. Yes. 27 1 Q. In what capacity? 2 A. As graduate research assistant. 3 Q. Were you doing anything in your work as a 4 graduate research assistant investigating central nervous 5 system chemicals? 6 A. No. 7 Q. When you were at Fort Wayne State Hospital, as I 8 understand it, you began and ended as director of research 9 at -- 10 JUDGE POTTER: Be sure and keep your voice up. 11 MS. ZETTLER: I never had a problem with that 12 before, Judge. 13 JUDGE POTTER: Why don't you back up a question, 14 Mr. Smith. 15 Q. When you were at Fort Wayne State Hospital, as I 16 understand it, you began and ended as director of research at 17 that institution? 18 A. That's right. 19 Q. And what was the research that you were 20 participating in at that institution? 21 A. It was in general aimed at understanding brain 22 dysfunction. 23 Q. Can you be more specific? 24 A. Well, the objective of the research program was 25 to understand the biochemical basis for brain dysfunction, 28 1 particularly mental retardation and psychiatric illness. And 2 the type of work that I did during the two-year period there 3 primarily involved measuring, doing analyses of body fluid 4 samples from mentally retarded subjects. 5 Q. When you say mentally retarded subjects, you are 6 drawing a distinction from those individuals who have mental 7 illnesses and disorders? 8 A. That's correct. 9 Q. In other words, these are individuals who, by 10 virtue of some unfortunate set of circumstances, did not have 11 the intelligence or were not able to develop to attain that 12 degree of intellect and functioning that most of us who are 13 normal attain; is that right? 14 A. That's correct. 15 Q. As opposed to individuals who have some 16 particular psychiatric disorder such as schizophrenia, 17 depressed individuals or other types of mental illnesses; is 18 that correct? 19 A. That's correct. 20 Q. Did you publish any works in connection with the 21 research you did on the biochemical basis of brain 22 dysfunction? 23 A. Yes, we did. 24 Q. And was it more than one work? 25 A. Yes, it was. 29 1 Q. How many were there? 2 A. I believe there were three papers altogether. 3 Q. Did you -- did any of those papers have to do 4 with serotonin or the serotonin system? 5 A. No. 6 Q. Did any of those papers have to do with 7 neurotransmitters specifically or generally? 8 A. No. 9 Q. Did you conclude based on your research and your 10 studies and your experience at Fort Wayne State Hospital that 11 mental dysfunction could have a biochemical basis in 12 individuals? 13 A. Well, that conclusion, I think, was fairly 14 obvious to those in the field before I began doing research 15 there. 16 Q. Was it generally recognized at the time you were 17 at Fort Wayne State Hospital that some mental dysfunction 18 could have a biochemical basis? 19 A. I think so. 20 Q. And were you of the opinion at that time that 21 some mental dysfunction could have a biochemical basis? 22 A. I'm not sure that I understand what you're 23 meaning by brain dysfunction could have a biochemical basis, 24 as opposed to what other kinds of basis. 25 Q. Maybe we need to define it, because I was using 30 1 terms that -- I wrote down terms that you had given me, and 2 maybe you would expand on that and describe for us in what 3 manner you're speaking of brain dysfunction and mental 4 dysfunction. 5 A. The brain, like other parts of the body, is made 6 up of molecules. And the function of any part of the body 7 involves molecular changes, so that when any part of the body 8 is dysfunctional there would be some type of molecular change 9 that would be occurring, and that would be as true for the 10 brain as any other part of the body, yes. 11 Q. Was it recognized then that some -- to use a 12 broad term -- that some mental illnesses were caused or had a 13 basis in some biochemical factor? 14 A. So far as I know, those people who were in the 15 field realized that there would be molecular abnormalities 16 whenever there was a functional abnormality, yes. 17 Q. You're familiar with the term personality 18 disorder? 19 A. Yes. 20 Q. Is that termed used by mental health care 21 professionals? 22 A. Yes. 23 Q. And are there some personality disorders that 24 have a biochemical basis? 25 A. I think all personality disorders would have a 31 1 disordered molecular processes going on. I don't think it's 2 meaningful to use the term "some." 3 Q. You think all -- 4 A. Yes. 5 Q. -- personality disorders have some biochemical 6 basis that causes this disorder? 7 A. I don't think you can separate thought and -- or 8 mental function and molecular changes as one causing the 9 other; they must occur together, I think. 10 Q. All right. Well -- 11 A. In other words, whenever -- I think there are 12 molecular changes occurring whether I think about them or not. 13 Q. Do those molecular changes cause you to think, 14 or is it because you think that there are molecular changes? 15 A. They're simply simultaneous occurrences. One 16 couldn't occur without the other. 17 Q. Well, I don't think about my heart beating. I 18 don't have to consciously cause a particular brain function to 19 cause my heart to beat; correct? 20 A. I would believe that, yes. 21 Q. Because you don't think to cause your heart to 22 beat, either, do you, Doctor Fuller? 23 A. That's correct. 24 Q. Our heartbeat is controlled by impulses from the 25 brain or impulses that originate from the brain, do they not? 32 1 A. It is influenced by that, certainly. 2 Q. But we don't have to consciously cause our heart 3 to beat, do we? 4 A. That's right. 5 Q. Our heart will beat when we're asleep; correct? 6 A. That's right. 7 Q. Our heart may beat faster as a result of being 8 afraid, mightn't it? 9 A. Yes. 10 Q. But we don't control that, either, do we, that 11 increase in heart rate by virtue of our perception of fear? 12 A. It would be the perception of fear that would 13 lead to the physiological changes that would cause the heart 14 to beat faster. 15 Q. That's not something that we think about, heart 16 beat faster, I'm afraid, is it? 17 A. I suspect that's true for most people. 18 Q. The same could be said for respiration; correct? 19 A. Yes. 20 Q. Digestion? 21 A. Yes. 22 Q. A function of many of our organ systems we 23 don't -- it's controlled by the brain or impulses that control 24 that originate from the brain, but we don't have to 25 consciously think about that; correct? 33 1 A. That's correct. 2 Q. Now, from that, there are -- can we move to 3 functions of the brain that dysfunction and result in physical 4 illness? For instance, are there diseases or anatomical 5 problems with the brain that can result in physical illness? 6 A. Yes. I'm sure there are. 7 Q. Can you give me some of those, an example of 8 something that is a disorder of the brain or nervous system 9 that results in physical illness? 10 A. I don't know that I can think of a particular 11 disease, if that's what you're looking for. 12 Q. How about polio? Doesn't that -- isn't that a 13 disease of the nervous system or an abnormality of the nervous 14 system that causes a physical illness? 15 A. You might say so, I think, yes. 16 Q. Epilepsy, is that a disorder of the brain or 17 nervous system that causes a physical illness? 18 A. I guess it depends on what you mean by physical 19 illness. 20 Q. Something that affects the physiological 21 function of the body that results in an abnormal condition. 22 A. Such as convulsions in that case? 23 Q. For instance, yes. 24 A. Sure. 25 Q. Now, are there brain dysfunctions or biochemical 34 1 bases for mental illnesses? 2 A. Again, there are. As Ralph Gerard said, behind 3 every crooked thought there lies a crooked molecule. 4 Q. Who is Ralph Gerard? 5 A. He was a very prominent neuroscientist. 6 Q. And he said beyond -- 7 A. Behind every crooked thought there lies a 8 crooked molecule. I think I'm quoting him correctly; that was 9 the thought. 10 Q. When Doctor Gerard made that statement, behind 11 every crooked thought lies a crooked molecule, what did he 12 mean by that as far as you understand the point he was trying 13 to make? 14 A. I think it's the same point I was making 15 earlier, and that is that the process of thought or motions 16 involve molecular changes and those are simply occurring 17 together and they can't be separated. 18 Q. So it's well recognized by you, as well as other 19 scientists knowledgeable in the field, that our thoughts and 20 the molecular changes in our brains are intertwined? 21 A. Yes. 22 Q. All right. Are you saying that a particular 23 molecular change can cause a particular thought? 24 A. I believe that could occur, yes. 25 Q. And is that generally accepted scientifically? 35 1 A. I think so. 2 Q. Can you list for me, Doctor Fuller, based on 3 your experience and your training and your research, some 4 mental disorders that have been established to be related to a 5 biochemical dysfunction in the brain? 6 A. Could you explain the question a little bit 7 more? 8 Q. Are there mental illnesses, as those conditions 9 have been described by psychiatrists -- schizophrenia, for 10 example -- are there mental illnesses that have as their basis 11 a biochemical mental dysfunction? 12 A. Are you asking a single biochemical change? 13 Q. Or a combination thereof. 14 A. I think most people believe that schizophrenia, 15 for example, is an example of such a disease, that abnormality 16 and dopamine function may be be one of the molecular changes 17 that is involved in schizophrenia. 18 Q. Any other mental illnesses? 19 A. I think depression is another example of a 20 mental illness where abnormalities and the function of one or 21 more transmitters is thought by many to be involved. 22 Q. That's part of what you do as a scientist, is it 23 not, Doctor Fuller, is try to get a greater understanding of 24 the effect or the relationship between mental dysfunctions and 25 some biochemical neurological change? 36 1 A. In a general sort of way, that is correct. 2 Q. How about paranoia? Does that -- would that be 3 a mental illness that has a biochemical basis, at least in 4 part? 5 A. I think that's often a subgroup of 6 schizophrenia. 7 Q. Can you define for us, please, what a 8 neurotransmitter is? 9 A. It's a substance that transmits signals or 10 messages from one nerve cell to another. 11 Q. Could you analogize a neurotransmitter to the 12 wiring in an electrical circuit transmitting energy from one 13 source to another in a very crude basis? 14 A. I don't think that's a very good analogy. 15 Q. Can you give me a little better analogy or can 16 you analogize it to something else that would give me, as a 17 layperson, a little better idea of what a neurotransmitter is, 18 Doctor Fuller? 19 A. I can try to describe neurotransmitters; I don't 20 immediately think of an analogy that would be helpful. 21 Q. All right. 22 A. But, fundamentally, the process of 23 neurotransmission is one nerve cell or neuron releasing a 24 substance which has an influence on an adjoining nerve cell, 25 and that is the process by which signals are transmitted from 37 1 one neuron to another. 2 Q. When you say signals, what do you mean by 3 signal? 4 A. I mean that this neuron receives, in essence, a 5 message or a signal. When a molecule of a particular 6 neurotransmitter acts on it, then it does something, whatever 7 it has been pre-programmed to do in response to that 8 particular signal. 9 Q. Is neurotransmission vital to brain function? 10 A. Yes. 11 Q. Are neurotransmitters divided or classified in 12 any particular way? 13 A. They are by some people. 14 Q. All right. What is the generally accepted 15 classification of neurotransmitters? 16 A. Well, for example, people often refer to 17 monoamine neurotransmitters, and by that they would include 18 serotonin, norepinephrine, dopamine, epinephrine and possibly 19 others. They might refer to neuropeptide neurotransmitters. 20 Q. That's a different class? 21 A. That would be a different class. 22 Q. What are some of those? 23 A. Substance P. 24 Q. Beg your pardon? 25 A. Substance P, capital P; enkephalin, endorphin, 38 1 neuropeptide Y and cholecystokinin. 2 Q. Okay. We've got monoamine neuropeptides. Any 3 other general classifications? 4 A. Well, there's different ways you might group 5 things so that there could be other classifications inspected, 6 I'm sure, but those are a couple of common ones. 7 Q. What is the reason for the different grouping of 8 those particular neurotransmitters into those one, two, three, 9 four broad categories? Is it based on their chemical 10 structure or based upon the derivation of making those 11 substances? How do you get that classification? 12 A. Those categories are based on chemical 13 structures. 14 Q. What was your first project with Lilly, 15 specifically? 16 A. It was to study a group of MAOIs that had been 17 synthesized by Jack Mills. 18 Q. Was serotonin involved in that? 19 A. Yes. 20 Q. Would that have been in 1963, when you began? 21 A. It began March 11th, 1963. 22 Q. Was that work done under Doctor Slater's 23 direction? 24 A. Yes. I assume you mean did I report to Doctor 25 Slater at the time I did the work. 39 1 Q. Yes. 2 A. Yes. The answer is yes. 3 Q. Have you done any work on serotonin, any 4 experiments involving serotonin prior to coming with Lilly in 5 1963? 6 A. No. 7 Q. Did that first work specifically involve 8 serotonin? 9 A. Yes. 10 Q. All right. And what specifically was that that 11 you did? 12 A. It was to measure the influence of MAOIs on 13 serotonin conservations in the brain of laboratory animals. 14 Q. Fluoxetine inhibits serotonin reuptake? 15 A. That's correct. 16 Q. When did you first begin work using the Lilly 17 compound that was later named fluoxetine? 18 A. 1972. 19 Q. And what did you first -- what did you do first 20 in connection with 110140 fluoxetine hydrochloride? 21 A. Well, let me explain that the molecule 22 fluoxetine was first synthesized as an oxalate salt, which has 23 a different number, 82816, so I assume you're asking me -- 24 you're not trying to make a distinction between 82816 and 25 110140? 40 1 Q. Right. 2 A. You're simply asking me what did I do first in 3 relation to this molecule? 4 Q. Yes. Was that in 1972 -- 5 A. Yes. 6 Q. -- when you first did any work in connection 7 with fluoxetine? 8 A. Yes. 9 Q. Okay. 10 A. I measured its effects on brain serotonin in 11 rats and mice and on serotonin metabolism and on the depletion 12 of serotonin by other drugs and on the effects of other drugs 13 on other monoamines. 14 Q. Who had synthesized fluoxetine? 15 A. Brian Molloy's laboratory. I think Brian 16 Molloy, with the assistance of Ken Houser. 17 Q. And Brian Molloy at that time was an employee of 18 Eli Lilly and Company? 19 A. Yes, he was. 20 Q. Did you have anything to do with the synthesis 21 of fluoxetine? 22 A. No, I did not. 23 Q. Did Doctor Wong have anything to do with the 24 synthesis of fluoxetine? 25 A. No, he did not. 41 1 Q. But you and Doctor Wong did some of the initial 2 work that established fluoxetine as a serotonin reuptake 3 inhibitor; isn't that correct? 4 A. That's correct. 5 Q. And explain to me what that work did. What was 6 your role that makes you kind of a co-founder or co-inventor 7 or co-developer of fluoxetine? 8 A. When Doctor Wong first found that fluoxetine, as 9 it was later called, inhibited the uptake of radioactive 10 serotonin by rat brain synaptosomes in vitro in the test tube, 11 we immediately began experiments to determine whether that 12 compound would inhibit serotonin uptake selectively in 13 animals, rats and mice. 14 Q. So Doctor Wong's first work was in vitro? 15 A. That's correct. 16 Q. Which is a scientific way of saying he was doing 17 it in the test tube and not using living organisms? 18 A. That's correct. 19 Q. Doctor Wong's work was in the test tube and your 20 work originally involved applying that knowledge or research 21 to living animals? 22 A. The initial work that we both did is as you 23 described it, yes. 24 Q. Okay. Specifically, what did you do first? 25 A. The first experiments that we did were to show 42 1 that this compound prevented serotonin depletion by 2 par-Chloroamphetamine, which was evidenced that it blocked the 3 serotonin uptake carrier in the rat brain in vitro, in the 4 mouse brain, and to show that it caused a decrease in 5 serotonin turnover as a result of that block of serotonin 6 uptake, serotonin turnover being measured by a decrease in the 7 brain concentration of the serotonin metabolite 8 5-hydroxyindoleacetic acid and measured in other ways, as 9 well, and it had these effects without blocking the uptake of 10 norepinephrine because it did not antagonize norepinephrine 11 depletion by drugs that depleted norepinephrine through a 12 carrier-dependent mechanism. 13 Q. Did you do that by exposing MAOIs to the 14 chemical fluoxetine? 15 A. We administered fluoxetine initially by 16 ingestion and in some experiments by oral gavage. 17 Q. Okay. First you injected a mouse with some 18 fluoxetine; is that correct? 19 A. We injected fluoxetine into mice, I believe is 20 the correct way of saying it. 21 Q. I may not say some things in the proper 22 scientific way, so bear with me. It's not my intent to 23 confuse you; I'm probably just confusing myself, Doctor 24 Fuller. 25 You injected some fluoxetine into a mouse. How 43 1 did you know how much fluoxetine to give to the mouse? 2 A. We gave various amounts to determine what amount 3 was effective in blocking the serotonin uptake carrier. 4 Q. All right. What was the first amount that you 5 injected? 6 A. I could not remember the precise doses in the 7 first experiment but, in general, the kind of doses that we 8 gave to rats and mice were between .1 and 10 milligram per 9 kilogram of body weight. 10 Q. How would that convert to an amount of 11 fluoxetine being given to a human? 12 A. The typical dose of fluoxetine in humans is 20 13 milligram per day, which would -- in a 60-kilogram human, 14 which would be about an average weight individual, would 15 translate to about .3 milligram per kilogram. 16 Q. So you were giving less or more? 17 A. We were giving a range on both sides of the dose 18 that is now used in humans. 19 Q. This wasn't, I assume, a toxic dose -- 20 A. These were not toxic doses. 21 Q. -- to mice? 22 A. That's correct. These were not toxic doses to 23 mice. 24 Q. You did later, I assume, or somebody at Lilly 25 did some toxicity studies; is that correct? 44 1 A. That is correct. Other people did. 2 Q. But this is -- what you were doing was even 3 earlier than the toxicity studies, you were trying to see 4 whether or not at a particular level you could demonstrate any 5 effect on the brain chemistry of a mouse? 6 A. That's correct. 7 Q. Before you gave fluoxetine to a mouse, Doctor 8 Wong had already demonstrated that it would inhibit its 9 serotonin reuptake by using just chemicals; is that correct? 10 A. No. He used what are called synaptosomes from 11 rat brain. 12 Q. But those synaptosomes were parts of rat brains 13 that hadn't been exposed -- 14 A. That's correct. 15 Q. -- while they were alive to fluoxetine? 16 A. That's correct. Initially, that's correct. 17 Q. And what you were doing was exposing mice to 18 fluoxetine while they were alive? 19 A. Mice and rats. 20 Q. And was this first experiment that you did an 21 experiment in any way to observe the behavior of rats or mice, 22 or was it simply to expose the rats and mice to fluoxetine to 23 be able to measure whether or not the chemical was inhibiting 24 the serotonin reuptake? 25 A. The primary purpose was the latter. We 45 1 certainly did observe the animals after we treated them, 2 however. 3 Q. Was there a specific protocol or experiment 4 outline that required that you observe the mice? 5 A. I don't understand what you mean by a protocol 6 that required it. We did the experiments all within my own 7 laboratory and we designed the experiments, and the 8 experiments were to administer the drug, and then at some 9 specified time interval thereafter, kill the animals and make 10 a measurement in their brain. And during the interval between 11 the time we injected the drug and the time we killed them, we 12 did observe them. 13 Q. Was there any written criteria with respect to 14 when you would observe those rodents and what particular 15 characteristics you would observe in those initial 16 experiments? 17 A. Not in any more detail than I just gave you, I 18 don't think. 19 Q. Were there any written records of what you 20 observed? Did you keep notes and say, you know, rats seem 21 sleepy, rats seem agitated, rats are not eating today, rats 22 are engaging in any particular behavior? 23 A. Yes. We always keep reports from the 24 experiments with any sort of -- with not only with all the 25 data that are measured, let's say serotonin concentration, but 46 1 anything that's noticed about the rat's behavior. 2 Q. What would you have done with those written 3 reports? 4 A. There weren't any behavioral observations with 5 fluoxetine. There weren't any behavioral changes that were 6 written down because there weren't any. In other words, you 7 couldn't tell any difference in fluoxetine-treated rats from 8 the controlled group. 9 Q. Regardless of the dosage that you administered? 10 A. That's correct. 11 Q. Did you subject the rodents to varying doses of 12 fluoxetine; correct? 13 A. Yes. 14 Q. Over the course of the experiment? 15 A. Yes. 16 Q. And did you subject the rodents to treatment of 17 fluoxetine over varying periods of time? 18 A. Yes. 19 Q. All right. Were the time periods that you were 20 employing -- all right. What were the time periods that you 21 were employing? 22 A. We measured -- whatever changes we observed, we 23 measured a full-time course on them to determine how long they 24 would last, and we used times anywhere between probably 30 25 minutes after treatment and 48 hours after treatment. 47 1 Q. So 48 hours was the longest period that you kept 2 the rodents alive from the time of first administration up 3 until the time you sacrificed the rat? 4 A. That may be true, again, picking that time from 5 memory, but for the most part I can -- what I remember is how 6 long the effects lasted. For example, the decrease in 7 5-hydroxyindoleacetic acid was still present at 24 hours, I 8 believe, and was not present at 48 hours. It's possible there 9 was a longer time than 48 hours that was included in the 10 measurement, as well, but I wouldn't remember that because the 11 effect didn't last that long. 12 Q. When you say the effect, you mean the serotonin 13 reuptake inhibition? 14 A. Well, the effect I referred to was one 15 particular consequence of that, the decrease in 16 5-hydroxyindoleacetic acid. 17 Q. When you say the decrease 5-hydroxyindoleacetic 18 acid, whatever it was that you said, are you talking about 19 serotonin levels being reduced? 20 A. No. 5-hydroxyindoleacetic acid is a metabolite 21 of serotonin. 22 A. The levels of 5-hydroxyindoleacetic acid are 23 reduced, levels of serotonin are not reduced. 24 Q. So by virtue of the -- is this called 5-HT? 25 A. Serotonin is commonly abbreviated 5-HT, 48 1 5-hydroxyindoleacetic acid is commonly abbreviated 5-HIAA. 2 Q. So your first study you were just measuring 3 5-HIAA, the metabolite? 4 A. No. In all those experiments we measured 5 both -- with serotonin, 5-HT, there is not a change in the 6 amount of serotonin as a result of uptake inhibition. There's 7 a change in the concentration of 5-HIAA, a decrease, and that 8 decrease I was saying persisted for 24 hours, but not 48 9 hours, after the administration of fluoxetine. 10 Q. Does that decrease in 5-HIAA mean that the 11 reuptake of serotonin is being inhibited? 12 A. That in conjunction with other experimental data 13 means just that, yes. 14 Q. But there is no change -- you found no change in 15 your measurements of the level of serotonin itself? 16 A. The concentration of serotonin itself, the total 17 tissue concentration didn't change; that's correct. 18 Q. Have you ever done any experiment where the 19 concentration did change of serotonin? 20 A. By and large, with serotonin uptake inhibitors 21 the tissue of levels of serotonin, the total amount of 22 serotonin tissue doesn't change. There may be a slight 23 increase at times but typically there's essentially no change. 24 Q. There were no studies that demonstrated any 25 change in serotonin levels; is that correct? 49 1 A. We have measured serotonin levels in the tissues 2 of rats and mice in many, many experiments with fluoxetine 3 over the years, sometimes measuring in whole brain, sometimes 4 measuring in particular regions of the brain, such as 5 hypothalamus, hippocampus, striatum cortex, something else 6 measuring at different times as early as 30 minutes, as long 7 as 48 hours or more. In most of those experiments, there was 8 not a statistically significant change in the amount of 9 serotonin. In some experiments, some brain regions at some 10 time, as I recall, there were small but statistically 11 significant increases in the amount of serotonin. That is not 12 an effect that one focuses on with serotonin uptake inhibitors 13 in general. 14 Q. Why is that, Doctor? 15 A. Because they don't cause changes in the amount 16 of serotonin. What they do is block the serotonin uptake and 17 increase its function, but the total amount of serotonin in 18 the brain doesn't change as a result of that, so that is not a 19 useful indicator of their effects. The useful indicator is 20 5-hydroxyindoleacetic acid. 21 Q. And so when that concentration of 5-HIAA goes 22 down, that means you're having a greater inhibition of 23 reuptake? 24 A. There could be other reasons for that going 25 down, but with a drug such as fluoxetine where you show in 50 1 other kinds of experiments that it does not do any of the 2 other things that might have led to that decrease, then the 3 decrease is an indicator of inhibition of serotonin uptake. 4 Q. So my original statement is basically correct or 5 generally correct? 6 A. Which original statement? 7 Q. The one where if you have generally levels of 8 5-HIAA going up, seeing increased levels of 5-HIAA, that means 9 that you're having an increase in serotonin reuptake? 10 A. No. That was neither your original statement 11 nor is that a correct statement. 12 Q. Okay. Help me then, Doctor Fuller. And, again, 13 I'm not trying to play word games with you and I'm not trying 14 to prove any particular point; I'm just trying to get some 15 knowledge of what appears to me to be an extremely complex 16 subject, which I am sure to you is like falling off a log 17 because you've been doing that -- because you're real smart, 18 Number One, and, Number Two, you've been doing it for a long 19 period of time. I don't fit in either classification, so I 20 need your help. 21 A. Let me restate it. When serotonin uptake is 22 inhibited, one consequence is a decrease in serotonin 23 turnover, one measure of which is a decrease in 5-HIAA 24 concentration. 25 Q. Is a decrease? 51 1 A. A decrease. So that with a drug such as 2 fluoxetine, the decrease in 5-HIAA is a measure of the dose 3 response effect on serotonin uptake and it's a measure of the 4 time course of the effect of serotonin. In other words, if 5 5-HIAA levels remain decreased for 24 hours, that indicates 6 the drug is inhibiting serotonin uptake for that period of 7 time. 8 Q. And is that what you found? 9 A. Yes, it is. 10 Q. What was the significance of this finding in 11 connection with the purpose of your research? 12 A. The significance of the collective results of 13 the experiments we did was to show that serotonin, that 14 fluoxetine was effective in blocking serotonin uptake in vitro 15 in rats and mice; that it had an adequate duration of action 16 and that it was selective in not blocking the uptake of other 17 monoamines. 18 Q. What is the importance of being selective in not 19 blocking the uptake of other neurotransmitters or is there any 20 importance? 21 A. Well, there can be importance in various 22 context. One scientifically interesting and exciting aspect 23 is at the time it was the first drug that had been discovered 24 that had this kind of selectivity. Drugs were known which 25 blocked serotonin uptake, but they didn't do so selectively; 52 1 they also affected the uptake of other neurotransmitters. 2 Having a drug that selectively blocked serotonin uptake then 3 provided a pharmacologic agent which would only increase 4 serotonin function, and that was useful to a scientist 5 interested in understanding more about the physiological role 6 of serotonin, and it was important in terms of the potential 7 usefulness of this agent as a drug. 8 Q. What was the -- what did you as one of the 9 initial researchers on this project see as some of the uses 10 that this drug could have? 11 A. Well, in 1972 and early 1973, which is the 12 initial period of study that we are talking about, it was 13 commonly believed that serotonin was an important 14 neurotransmitter in depression and that the action of the 15 antidepressant drugs which were available at that time 16 probably importantly involved serotonin. So, clearly, the 17 potential use as an antidepressant drug was apparent and, in 18 addition, serotonin had been postulated to be possibly 19 important in some other psychiatric diseases, such as 20 schizophrenia and obsessive compulsive disorder, and it was 21 also believed that enhancing serotonin function would reduce 22 appetite and be a useful treatment for obesity, and those were 23 some of the therapeutic applications that we considered. 24 Q. Had it been demonstrated prior to 1972 and 1973 25 that fluoxetine -- that serotonin as a neurotransmitter had 53 1 effect on appetite or was that something that you found, 2 Doctor Fuller? 3 A. There was evidence that serotonin affected 4 appetite, yes. 5 Q. Do you recall what the nature of that evidence 6 was? 7 A. Well, for example, one piece of evidence was 8 that there was a drug, which was, I believe, already marketed 9 at that time called fenfluramine, which was thought to act by 10 increasing serotonin function. 11 Q. And had an effect on appetite? 12 A. Yes. 13 Q. All right. Was there any evidence in existence 14 at that time that serotonin would or could have an effect on 15 -- or serotonin level could be implicated in schizophrenia or 16 obsessive compulsive disorder? 17 A. Yes. For example, Richard Wyatt and colleagues 18 at the National Institute of Mental Health were publishing 19 papers at that time based on the administration of the 20 serotonin precursor, L-5-hydroxytryptophan. 21 Q. When you say precursor, explain to us what you 22 mean by that. 23 A. L-5-hydroxytryptophan is the immediate precursor 24 before serotonin. That is L-5-hydroxytryptophan is converted 25 to serotonin in the body. It is part of the pathway by which 54 1 the body makes serotonin. And L-5-hydroxytryptophan is an 2 amino acid which can be given and that crosses the blood brain 3 barrier and be converted to serotonin in the brain. And Dick 4 Wyatt and his colleagues were giving 5-hydroxytryptophan to 5 chronic schizophrenic patients and reporting beneficial 6 therapeutic benefit and interpreting the enhancement of 7 serotonin function could be useful in treating schizophrenia. 8 Q. Do you have an opinion in connection with 9 respect to whether or not fluoxetine would be useful as an 10 appetite suppressant? 11 A. There are clearly published studies that suggest 12 it is useful, yes. 13 Q. Have you done any studies in that connection? 14 A. What I'm referring to here are studies in humans 15 and, no, I have not done any studies on humans. 16 Q. Do you have an opinion concerning whether or not 17 fluoxetine can be useful as a therapy for appetite control? 18 A. Yes. Based on those published studies that I 19 just referred to. 20 Q. And what is that opinion? 21 A. It appears to be useful. 22 Q. What is it about fluoxetine that causes 23 inhibition of the reuptake of serotonin? 24 A. It interacts directly with the serotonin 25 transporter. I'm not sure if there's something you're asking 55 1 beyond that or not. 2 Q. How does it act together with the serotonin 3 transporter? 4 A. It occupies the position on the serotonin 5 transporter where serotonin would normally occupy it to be 6 transported and therefore the serotonin can't be transported. 7 Q. When you say transporter, do you mean receptor 8 site? 9 A. No. The term receptor, as I have used it and is 10 used conventionally in neuropharmacology, refers to a site on 11 the neuromembrane which elicits some particular response in 12 the neuron. The term transporter is a different type of 13 macromolecule, the function being to actually transport 14 something from one side of the cell membrane to the other 15 side, so a transporter and a receptor are different entities. 16 Q. What is the transporter of serotonin? 17 A. What is it? 18 Q. Yeah. 19 A. It is a protein macromolecule that exists on the 20 serotonin nerve membrane. 21 Q. What's it called? 22 A. It's called the serotonin transporter on the 23 serotonin uptake carrier. 24 Q. I'm having a little difficulty completely 25 understanding this, and Doctor Wong drew for us a diagram that 56 1 helped us, I thought at the time, describing the neurons in 2 connection with a serotonin system and a nerve in a brain and 3 how the serotonin moved past the synaptic cleft and into the 4 next -- moved from the presynaptic neuron to the postsynaptic 5 neuron. Can you give us a visual demonstration of that? 6 A. Well, I could draw a diagram similar to what 7 I've published in a number of my publications. 8 Q. Would you do that for us? 9 A. I'm sure you've seen that. If that would be 10 helpful, I can try to reconstruct it. 11 Q. Please. And, again, we're looking for some kind 12 of understanding of this subject that -- 13 A. These are the events that go on at the -- I'm 14 not an artist, please understand, but I'm drawing a diagram to 15 illustrate the kind of events that go on at a serotonin 16 synapse, and in this diagram this structure is intended to 17 represent a serotonin nerve terminal that is making synaptic 18 contact with some sort of target neuron over here, and the 19 whole purpose of this connection is that this neuron can send 20 a signal to this neuron by means of molecular serotonin, and I 21 typically draw this by using the abbreviation 5-HT to indicate 22 serotonin. The 5-HT is the chemical -- is the abbreviation 23 for the chemical name for serotonin, which is 24 5-hydroxytryptamine, and that serotonin is synthesized within 25 the nerve. 57 1 Q. When you say synthesized within the nerve, you 2 mean serotonin is actually manufactured there in the nerve? 3 A. That is correct. 4 Q. Okay. Is that where the precursor comes in? 5 A. Exactly. The precursor that I mentioned before 6 is 5-hydroxytryptophan, which is usually abbreviated 5-HTP, 7 and it is formed from the amino acid tryptophan, which I will 8 just call TRY, and the serotonin that is formed here -- 9 Q. Is that the purpose of this neuron, the 10 serotonin neuron, to manufacture and then transport serotonin? 11 A. It certainly is one of its purposes. 12 Q. Is its function for additional purposes? 13 A. That's probably its major purpose. I say that 14 because an individual neuron might be manufacturing more than 15 one neurotransmitter, for example. 16 Q. All right. 17 A. The serotonin is taken into storage granules or 18 vesicles, which I will just illustrate with a little circle 19 around it, and these then are where the serotonin is actually 20 released from the nerve impulse out in the synaptic space or 21 synaptic gap. 22 MR. SMITH: Your Honor, at this time we'd like 23 to introduce the drawing that Doctor Fuller is referring to. 24 JUDGE POTTER: What's this number, Mr. Smith? 25 MR. SMITH: It's marked as Fuller Exhibit 33, 58 1 Plaintiffs' Exhibit 33. 2 JUDGE POTTER: Plaintiffs' 33. If you'll hand 3 it to my sheriff, she'll pass it around. Be admitted. 4 SHERIFF CECIL: (Hands document to Jurors). 5 MR. SMITH: Why don't we back up on Page 96 and 6 read beginning of Line 20. 7 Q. All right. 8 A. The serotonin is taken into storage granules or 9 vesicles, which I will just illustrate with a little circle 10 around it, and these then are where the serotonin is actually 11 released from the nerve impulses out into the synaptic space 12 or synaptic gap. 13 Q. Or cleft? 14 A. Or cleft; right. Now, there are some serotonin 15 neurons that probably aren't making a tight synaptic contact 16 with the postsynaptic cell but just have a variety of neurons 17 around it. But I'm just illustrating -- but I'm just 18 illustrating the events that go on rather than -- this is not 19 intended to be anatomically correct in all cases. And so 20 there would be some serotonin out there in this extracellular 21 space, the synaptic cleft, where there is a tight synaptic 22 junction. 23 And on this neuron there would be a receptor of 24 some sort which would be sensitive to serotonin. In other 25 words, serotonin would uniquely interact with this particular 59 1 part of a molecule so that this molecule would know it had 2 received a signal from serotonin. 3 Q. Okay. 4 A. And it would do something then in response to 5 that. It could be -- it would be whatever this neuron had 6 been preprogrammed to do in response to that. It might be to 7 speed up or slow down or do something differently. And then 8 the serotonin is inactivated by being taken out of the 9 synaptic cleft through the action of the type of molecule that 10 I have referred to as a transporter or an uptake carrier, 11 which I often draw something like this to indicate sort of 12 something that's taking serotonin from out here and putting it 13 back in here. 14 Q. Is that molecule located on the end of the 15 neuron, that uptake? 16 A. It's probably located -- it's located on the 17 outer membrane of the neuron, probably various places around 18 it. And once the serotonin is back inside, then it's already 19 out of contact with this receptor. 20 Q. So it doesn't act as a neurotransmitter -- the 21 neurotransmission must occur in the synaptic cleft; is that 22 what you're saying? 23 A. Must occur outside the neuron, as I just said. 24 It may occur in a tight synaptic cleft or there could be just 25 another system, another place in the brain where there isn't 60 1 this tight synaptic cleft, but, rather, there's other neurons 2 around out here somewhere that the serotonin neuron reaches. 3 Q. Okay. Well, we'll -- 4 A. But in general what you say is correct. 5 Q. All right. 6 A. And the serotonin that is back inside the neuron 7 then can either be reused or it can get destroyed by this 8 enzyme that we talked about earlier called monoamine oxydase, 9 and the major product of that action is what we have referred 10 to as 5-HIAA, 5-hydroxyindoleacetic acid. 11 Q. So when we see or measure 5-HIAA as you did in 12 your experiments initially -- 13 A. Yes. 14 Q. -- you were measuring how much serotonin was 15 actually being converted to -- would waste be the proper term 16 or another -- 17 A. Converted to -- 18 Q. -- inactive chemical as a neurotransmitter? 19 A. Converted to 5-HIAA is what was happening. 20 Q. 5-HIAA is not a neurotransmitter? 21 A. That is correct. 22 Q. Once serotonin becomes 5-HIAA it no longer is 23 useful as a neurotransmitter? 24 A. So far as we know, that is correct. 25 Q. And what does the body do with 5-HIAA? 61 1 A. It ends up excreting it in the urine. 2 Q. So 5-HIAA is a waste product of this 3 neurotransmission system that we have in our brains? And when 4 I say waste product, I don't mean it in some garbage dump; I 5 mean it's just a product that's no longer useful to the human 6 body in neurotransmission. 7 A. It is a product that is no longer useful to the 8 human body and neurotransmission, so far as we know. 9 Q. Go ahead. I'm sorry. I didn't mean to 10 interrupt you. 11 A. That essentially is some of the major events 12 that go on. Obviously, there are lots of other things that go 13 on in any cell in the body, but these are some of the key 14 events that are unique to a serotonin neuron. 15 Q. You have depicted two neurons; is that right? 16 A. Yes. 17 Q. Is one neuron called the presynaptic neuron and 18 another neuron called the postsynaptic neuron? 19 A. When you're talking about a particular synaptic 20 junction, this one would be called the presynaptic neuron and 21 this would be called the postsynaptic neuron. 22 Q. Well, this postsynaptic neuron doesn't 23 manufacture and store serotonin, does it, or does it? 24 A. There's no law that says it could not also be a 25 serotonin-containing neuron, but it would not necessarily be a 62 1 serotonin-containing neuron. 2 Q. But in the process of neurotransmission, the 3 postsynaptic neuron doesn't act as a manufacturer and storer 4 of serotonin; is that correct? 5 A. As I just said, the postsynaptic neuron could be 6 another serotonin neuron or it might be a neuron that made 7 some other neurotransmitter. 8 Q. Could we in fact have a line where this 9 postsynaptic neuron in the chain of things is just like the 10 presynaptic neuron, it also is performing the function of 11 manufacture and storing and firing on serotonin on down the 12 line? Am I making it too simple or too complex? 13 A. Let me try to give you some context for this. 14 Q. Do you want to draw? 15 A. No. I don't want to draw another picture. In 16 the brain, each neuron is sending signals to many other 17 different neurons and is receiving signals from many different 18 neurons. What we are looking at here is just one synaptic 19 contact between one neuron and another. The same neuron may 20 be sending signals to 50 other neurons or 100 or something 21 like that. 22 Q. Would those other signals be other 23 neurotransmitters like dopamine, epinephrine and things of 24 that nature? 25 A. Let's suppose we are talking about one 63 1 particular serotonin neuron, and let's suppose that this 2 particular neuron was actually sending signals to 87 different 3 neurons. I just picked the number obviously out of the blue. 4 Could any one of those 87 be another serotonin neuron? Sure, 5 it could. The chances are that most of them, however, are 6 neurons that could use a variety of other neurotransmitters. 7 Q. All right. Can this pre- and postsynaptic 8 neuron be seen on a microscope? 9 A. Yes. Can a synaptic -- you're asking can a 10 synaptic junction be seen microscopically? 11 Q. Yes. 12 A. Yes. 13 Q. What is the distance -- to get some kind of 14 concept of what we're talking about, can you give me the 15 distance between -- within the synaptic cleft? 16 A. It would be measured in micrometers. It's a 17 very, very small distance. 18 Q. All right. Has the volume of that substance at 19 a particular synaptic cleft ever been measured? 20 A. Within one individual synaptic cleft? 21 Q. Yes, sir. 22 A. No, not to my knowledge. 23 Q. Would that be something that could be done 24 scientifically? 25 A. No. Not to my knowledge at the present time. 64 1 Q. We just don't have the technology to do that? 2 A. That's correct. 3 Q. Would it be of any scientific significance or 4 importance the volume or amount of serotonin that exists 5 within this synaptic cleft? 6 A. The amount of serotonin that exists is certainly 7 of interest. 8 Q. Why is that, Doctor Fuller? 9 A. It's because what's important in the process of 10 neurotransmission is not how much serotonin is sitting here in 11 the vesicle. 12 Q. That's where it's stored? 13 A. Where it's stored. But, rather, how much is 14 actually transmitting a signal. 15 Q. Why is that important? 16 A. Why is that? 17 Q. Let me say it this way: How does the amount of 18 volume affect the quality or quantity of the signal? 19 A. You're using the term volume I think in a way 20 that isn't conventionally used. Volume ordinarily means the 21 size of something or how much space it occupies. The number 22 of serotonin molecules, for example, or the concentration of 23 serotonin here in the synaptic cleft, I think is what you 24 mean, is what determines how much transmission is occurring 25 via that particular synapse. 65 1 Q. Why does that particular concentration affect 2 how much transmission is going on? Why is it that there are 3 more -- the higher the concentration the more transmission 4 you're going to get? 5 A. Well, the higher the concentration out here, the 6 more this receptor is going to be activated. 7 Q. What is this receptor doing actually? 8 A. It's transmitting -- transducing a signal. 9 Whenever it is acted on by a serotonin molecule it triggers 10 some event within this neuron which causes that neuron to do 11 something differently. 12 Q. Is it actually moving a serotonin molecule from 13 the synaptic cleft into the receptor site into the 14 postsynaptic neuron? 15 A. No. So far as we know, the serotonin molecule 16 only acts on the surface of this receptor, and it causes that 17 receptor to change in conformation or some way which then 18 leads to some molecular changes inside the neuron. 19 Q. Serotonin isn't moving across from one neuron to 20 another neuron; is that what you're saying? 21 A. No, that's not what I'm saying. 22 Q. Okay. 23 A. And that is not what you said. What you said 24 and I agree with is that serotonin does not move into that 25 neuron; it indeed moves from this storage site into the 66 1 synaptic cleft and then is removed primarily by being 2 transported back inside. So, as far as we know, it does not 3 enter that neuron. 4 Q. So the effect that is important is the effect on 5 the postsynaptic neuron's receptor site; is that correct? 6 A. That effect is important. 7 Q. Because that is neurotransmission, isn't it, 8 Doctor Fuller? 9 A. That's correct. 10 Q. The activation of serotonin on the receptor site 11 is neurotransmission? 12 A. In regard to the synapse; right. 13 Q. Yes. 14 A. In general, the neurotransmission is the action 15 of a transmitter on some receptor site to cause the target 16 neuron to do something. 17 Q. Now, what kinds of messages does serotonin 18 transport to the receptor site? 19 A. Well, it -- in terms typically a message of this 20 sort is translated through some second messenger pathway and 21 common second messengers would include cyclic AMP and a 22 neurotransmitter, when acting on a receptor, might cause an 23 increase or decrease in the amount of cyclic AMP inside this 24 neuron. 25 Q. What is cyclic AMP? 67 1 A. It is a cylcic nucleotide made up of adenosine, 2 ribose and phosphate and it's simply one of the body's common 3 so-called second messengers. 4 Q. What does it do? 5 A. It causes some event to take place in the cells. 6 Q. We're trying to take your deposition, but we're 7 also trying to learn from you and you're trying to explain to 8 us, and I appreciate that, and don't let me cut you off. 9 A. The changes in cyclic AMP cause further 10 molecular changes then. They -- it could lead to a conversion 11 of an active enzyme into an inactive form or vice versa. The 12 point is it is called a second messenger because it changes in 13 response to a receptor activation and then it leads to further 14 changes of some sort. 15 Q. How does that neurotransmission of serotonin at 16 the receptor site affect the way we think or feel or the way 17 we react? 18 A. Well, we are thinking and feeling and reacting 19 because of a very complex series of molecular changes of this 20 exact sort that are going on within our brains, and it is the 21 composite of those which causes us to have particular changes 22 or feelings or thoughts. If I have a different thought now 23 than I had a few minutes ago, it is because there's a 24 different summation of neurotransmission that's going on. 25 Q. As I understand it, neurotransmission occurs at 68 1 the receptor site; correct? 2 A. It begins at the receptor site. 3 Q. But as far as this illustration you've drawn us, 4 the transfer -- 5 A. Uh-huh. The transfer. 6 Q. -- must occur at the receptor site? 7 A. Yes. 8 Q. So that's where neurotransmission occurs. 9 That's where the effect of all this process is? 10 A. Okay. 11 Q. Is that correct scientifically? 12 A. That's correct, as long as you're sort of 13 defining neurotransmission that far. You could also think of 14 neurotransmission in a more global sense, but go ahead. 15 Q. I don't mean to imply that, because I believe 16 the entire basis of your research and what you found is that 17 if you can increase the concentration of serotonin in the 18 synaptic cleft you can affect the ability of the receptor site 19 to pass on the serotonin message; is that right? 20 A. That is part of my research. My research is 21 much broader than that in general. 22 Q. I understand that. But that's supposedly the 23 beneficial effect of fluoxetine? 24 A. As far as we know, the action of fluoxetine is 25 to inhibit that transporter and cause an increased number of 69 1 serotonin molecules to be in the synaptic cleft. 2 Q. And the increase in the amount of serotonin 3 molecules in the synaptic cleft affects the receptor site? 4 A. Yes. 5 Q. Now, what holds the serotonin within the 6 synaptic cleft? The reason I ask that is there is a space 7 obviously on the top and there's a space on the bottom, and I 8 understand that you're not drawing this according to any 9 perfect anatomy, but can you give us an explanation as to how 10 the serotonin stays within the synaptic cleft? 11 A. Well, there are no forces that hold it within 12 the synaptic cleft. Every molecule of serotonin that enters 13 the synaptic cleft could leave by prediffusion, for example. 14 The evidence is that the bulk of it, however, is actively 15 transported by the uptake carrier before it has time to 16 diffuse away. 17 Q. So there is indeed spaces within the synaptic 18 cleft that a certain number of serotonin molecules can escape 19 out of? 20 A. There is no physical barrier to it escaping. 21 Q. Have there been any studies or any experiments 22 done to determine the percentage of serotonin within the 23 synaptic cleft that is transported or taken back into the 24 presynaptic neuron versus that amount that could diffuse out 25 of that area? 70 1 A. No, not to my knowledge. 2 Q. Would that be something that would be of 3 scientific interest? 4 A. Yes, it would. 5 Q. Well, do you think that the reuptake by the 6 reuptake side on the presynaptic neuron prevents loss of 7 serotonin from the synaptic cleft? 8 A. The physiologic purpose of the uptake is not 9 thought to be one of preventing loss or preservation but, 10 rather, one of terminating the action once the serotonin has 11 had a chance to come in contact with the postsynaptic 12 receptor. 13 Q. Why is there a reason to terminate the action? 14 A. Well, please understand I didn't design the 15 system, but a possible explanation is simply what one wants to 16 do is send discreet signals and you want to be able to limit 17 the duration of those signals. 18 Q. Well, it's my understanding that the system of 19 reuptake, at least in part, is not to preserve serotonin or 20 prevent it from leaving the synaptic cleft, but to do 21 something to limit the message that is being transported to 22 the receptor site; is that right? 23 A. Yes. I think that's right. To provide for a 24 certain degree of activation of the postsynaptic receptor. 25 Q. Why is that important to have a limit on the 71 1 activation of the postsynaptic nerve receptor? 2 A. I think all I can do is describe the system as 3 it exists in nature to the best of our understanding without 4 speculating on why it happens to be that way. 5 Q. Okay. And I think -- have we pretty well 6 described the system, at least so far? 7 A. I think the essence of the system has been 8 described. 9 JUDGE POTTER: From the sound of the last 10 questio and answer, this seems like a good time to break. Is 11 that all right? 12 MR. SMITH: Okay. 13 JUDGE POTTER: Ladies and gentlemen, we're 14 going to take a 15-minutes recess. As I've mentioned to 15 you-all before, do not permit anybody to speak to you or 16 communicate with you on any topic connected with this trial 17 and any attempt to do so should be reported to me. Don't 18 discuss the case among yourselves or form or express opinions 19 about it. We'll stand in recess for 15 minutes. 20 (RECESS) 21 SHERIFF CECIL: The jury is now entering. All 22 jurors are present. 23 JUDGE POTTER: Please be seated. Ladies and 24 gentlemen of the jury, we're going to do something that's a 25 little out of the ordinary, but I hope it will help you. 72 1 Doctor Thompson is not going to be placed under oath, but the 2 attorneys and whatnot know this diagram fairly well, and what 3 Mr. Smith is going to do is ask him a few questions and he 4 will point out on the diagram that's on the television, which 5 is the same diagram that you-all have there, as to what the 6 various parts of that diagram are so that you will understand 7 it better as they're reading the deposition of Doctor Fuller. 8 Go ahead, Mr. Smith. 9 MR. SMITH: All right. Doctor Thompson, we've 10 discussed the presynaptic neuron is where? 11 DOCTOR THOMPSON: That's this entire structure 12 there. 13 MR. SMITH: And the postsynaptic neuron would be 14 where? 15 DOCTOR THOMPSON: That's the structure right 16 there. 17 MR. SMITH: The synaptic cleft, where would that 18 be located, Doctor Thompson? 19 DOCTOR THOMPSON: Between those two nerve cells. 20 MR. SMITH: And the receptor site that the 21 fluoxetine comes on to block reuptake and serotonin? 22 DOCTOR THOMPSON: That's a bit more difficult. 23 This is not where the fluoxetine works. The serotonin works 24 in the receptor right there. The fluoxetine blocks the 25 reuptake mechanism right there. 73 1 MR. SMITH: You'd call that a transporter; is 2 that right? 3 DOCTOR THOMPSON: Yes, sir. Correct. 4 MR. SMITH: The vesicles that Doctor Fuller is 5 talking about, where would that be located as he drew it 6 there? 7 DOCTOR THOMPSON: That's one of the vesicles 8 containing the 5-HT. 9 MR. SMITH: Anything else about the anatomy of 10 Doctor Fuller's drawing that you think would be helpful for 11 the jury to see? 12 DOCTOR THOMPSON: Well, in this nerve cell, 13 tryptophan, a normal amino acid gets made in 14 5-hydroxytryptophan, which then gets turned into 5four had it, 15 which we call as a slang term serotonin, and it gets into this 16 vessel or it can be tab licensed. If HIAA by an enzyme called 17 monoamine oxydase, MAO. 18 MR. SMITH: All right. And the 19 neurotransmission is occurring from the presynaptic to the 20 postsynaptic neuron? 21 DOCTOR THOMPSON: Yes, sir. Serotonin would be 22 replaced from the vesicle into the cleft, it would activate 23 this receptor which along with all the other things going on 24 would lead to an electrical signal going down this nerve. 25 MR. SMITH: Thank you, Doctor Thompson. 74 1 JUDGE POTTER: Thank you, sir. 2 Mr. Smith. 3 MR. SMITH: Resuming the deposition of Doctor 4 Ray Fuller on Page 118, beginning Line 16. 5 Q. Okay. And I think we have pretty well described 6 the system, at least so far? 7 A. I think the essence of the system has been 8 described. 9 Q. Fluoxetine works on the reuptake receptor site; 10 is that correct? 11 A. That is correct. 12 Q. Is the reuptake receptor site a physical place 13 on the presynaptic neuron? 14 A. Well, let me again point out that, one, a 15 neuropharmacologist would not use the term receptor in that 16 context. The transporter site is ordinarily referred to as 17 separate from the receptor site. The transporter would be a 18 particular macromolecular complex within the cell membrane. 19 Q. And it would have a particular anatomical 20 location? 21 A. Yes. 22 Q. On the cell membrane; is that correct? 23 A. Yes. 24 Q. And the action of fluoxetine is to act on that 25 transporter; is that correct? 75 1 A. To interact with it, yes. 2 Q. So we've got a receptor receiving the serotonin 3 messages; correct? 4 A. That is correct. 5 Q. That we have described on the postsynaptic 6 neuron? 7 A. Yes. 8 Q. And then we've got a transporter that is drawn 9 on the presynaptic neuron with a circle with an X in it; is 10 that right? 11 A. That is correct. That is not to imply that 12 receptors don't also occur on the presynaptic neuron, however. 13 Q. All right. Would those be receptors of 14 serotonin? 15 A. Yes. There are serotonin receptors also present 16 on serotonin neurons themselves and these are usually called 17 autoreceptors. 18 Q. What is their function? 19 A. Their function is believed to be to sense the 20 concentration of serotonin in the synaptic cleft and to 21 regulate the further release and synthesis of serotonin within 22 that neuron. 23 Q. We were going to get to that because I was going 24 to back up and say, well, what starts the process to begin 25 with, that is, the discharge of the serotonin from this 76 1 storage area out in the synaptic cleft, and it is your 2 testimony that there are autoreceptors that are located on the 3 presynaptic neuron that affect this procedure and start this 4 procedure? 5 A. I wouldn't use the word starts that procedure, 6 but they certainly do influence that procedure. 7 Q. Would "regulate" be an accurate term? 8 A. Yes, it would. 9 Q. Can you draw an autoreceptor? 10 A. It will look much like a postsynaptic receptor. 11 Q. Why don't you make it in a star or something? 12 A. I will. 13 Q. A diamond, you know, make it a little -- okay. 14 Does fluoxetine in any way work on the autoreceptor? 15 A. No, not so far as we know. 16 Q. Does fluoxetine work in any way in any manner on 17 the postsynaptic receptor? 18 A. Fluoxetine does not directly interact with 19 either the presynaptic or postsynaptic receptor. By 20 interacting with the transporter it alters the amount of 21 serotonin that interacts with those receptors. 22 Q. But that's an indirect action? 23 A. The action of fluoxetine on the transporter is a 24 direct action. The consequence of that direct action is an 25 increase in the amount of serotonin, which acts on the 77 1 postsynaptic receptor. 2 Q. The theory in connection with the use of 3 fluoxetine for treatment of depression, as I understand it, is 4 that some individuals do not have enough serotonin present in 5 the synaptic cleft; is that right? 6 A. That is one theory. 7 Q. Is there any scientific data on why some 8 individuals would have an inadequate amount of serotonin 9 within the synaptic cleft and others would have an adequate 10 amount? 11 A. There have been many published studies in which 12 scientists have measured the amount of serotonin in brain 13 samples obtained at autopsy from patients who died and had 14 depression. In relation to patients who died but were not 15 depressed of similar -- and they were patients of similar age 16 and sex and so on, there is evidence from some studies that 17 the concentration of serotonin may be reduced in the brains of 18 depressed patients so that there may be less stored serotonin 19 available for release in some depressed patients. 20 Q. Can you give me a name of a study that comes to 21 mind? Are those studies back as early as the '50s and the 22 '60s? 23 A. Many of the studies were done quite a number of 24 years ago, yes. 25 Q. All right. We have those. The scientific 78 1 thought is, is that the rereason for this deficiency in the 2 serotonin available at the synaptic cleft is by virtue of an 3 inadequate amount of storage in the storage sites that hold 4 serotonin? 5 A. That would be one possible explanation and that 6 would be the explanation that would be supported by the 7 particular studies that I just mentioned, yes. 8 Q. Are there other explanations as to why some 9 individuals have, that account for some individuals having 10 less serotonin than others? 11 A. No. I don't know that there is other 12 explanations that could be supported with data. 13 Q. Has there been any research to determine whether 14 or not diet has an influence on the amount of serotonin 15 available within the storage facilities? 16 A. Yes. There has been such research. 17 Q. And what is the result of that research as to 18 whether or not diet can be a cause of a shortage of serotonin? 19 A. I think the overall evidence is that dietary 20 changes have been shown to have modest influences on the 21 amount of serotonin. Obviously, tryptophan being the 22 precursor of serotonin, any diet that was grossly deficient in 23 tryptophan would certainly impair the synthesis of serotonin, 24 for example. 25 Q. Have there been any studies of any individuals, 79 1 humans, that have for some reason or another had a diet that 2 is grossly insufficient of tryptophan? 3 A. Yes. There are certainly some countries in 4 which the type of protein that's consumed is relatively low in 5 tryptophan and there can be nutritional as a result of that. 6 The consequences, generally, however, are not principally 7 related to serotonin. Tryptophan is required for synthesis of 8 all proteins and it has other functions in the body, so that 9 results of tryptophan deficiency would not necessarily 10 principally be caused by a shortage of serotonin. 11 Q. Certainly those people by virtue of their 12 insufficient diet have problems that are other than problems 13 of depression and related to problems with the serotonin 14 system? 15 A. Severe shortage of tryptophan certainly will 16 produce a multitude of problems. 17 Q. Is there any thought that by basis of genetics 18 some of us that maybe inherited with an impaired ability to 19 produce or store serotonin? 20 A. That sort of possibility certainly has been 21 considered. There is not evidence that occurs to me at the 22 moment that would say that's the major determinant. 23 Q. In other words, the theory, based on these 24 studies back in the '60s -- even maybe as early as the '50s, I 25 don't recall -- was that there was less serotonin found at 80 1 autopsy and at spinal taps of individuals who had met with 2 suicide deaths as opposed to those who had died of natural 3 diseases in that there was a finding that they had less 4 serotonin in their cerebrospinal fluid; is that correct? 5 A. Well, I think you've mixed several types of 6 studies together. 7 Q. Don't let me. 8 A. There have been studies of serotonin contents in 9 autopsy brain samples. These are not necessarily studies in 10 patients who died of suicide, although some of them I think 11 were. Some patients who are depressed do die of suicide; some 12 patients who are depressed die of other causes, and there have 13 been studies that are focused on depressed patients who died, 14 but not of suicide, in which serotonin content in autopsy 15 brain sample was measured. There have been other studies 16 which I think you are referring to in which the cerebrospinal 17 fluid obtained by spinal tap there were measurements, but in 18 that case it was not serotonin that was being measured; it was 19 the concentration of 5-HIAA, the serotonin metabolite. And in 20 some of those studies there were findings that, at least in 21 some depressed patients, there was a lower-than-normal 22 concentration of 5-HIAA in the cerebrospinal fluid, and in 23 some studies there is evidence that this is particularly true 24 of patients who are suicidal as opposed to patients who are 25 not suicidal. So there are several different kinds of studies 81 1 that have been done. 2 Q. And it's those studies that form the sole basis 3 in humans that depression may be related to low levels of 4 serotonin or low levels of its metabolite -- or measured or 5 low levels of serotonin, just leave it at that? 6 A. I would answer by saying no, that is not the 7 sole basis for the interest in the belief that serotonin is 8 important in depression. 9 Q. What other evidence is there? 10 A. An important line of evidence separate and 11 distinct from those was the findings that drugs that were 12 effective in treating depression, including the monoamine 13 oxydase inhibitors and the so-called tricyclic antidepressant 14 drugs, which are uptake inhibitors, the fact that they were 15 effective in treating depression, alleviating symptoms of 16 depression, coupled with the knowledge that they did affect 17 serotonin; they didn't affect serotonin specifically, they 18 affect other monoamines, as well, but among the monoamines 19 they will affect is serotonin. So that knowledge, when it's 20 interpreted as further evidence that implicated serotonin as 21 an important neurotransmitter in depression. Again, it 22 doesn't necessarily mean that a low serotonin concentration is 23 the cause of depression, but it supports the idea that if you 24 can enhance serotonin function you can alleviate depressive 25 symptoms. 82 1 Q. Is serotonin present in cerebrospinal fluid? 2 A. There's very little serotonin in cerebrospinal 3 fluid. That's why what is measured in the cerebrospinal fluid 4 is the metabolite 5-HIAA. 5 Q. Is the reason that there is very little in 6 spinal fluid because most of the serotonin is used in 7 neurotransmission and the rest of it -- almost all the rest of 8 it is stored? 9 A. Probably the reason that there's so little in 10 the cerebrospinal fluid is that it is metabolized once it is 11 released from the storage granules. It is metabolized before 12 it reaches the cerebrospinal fluid. So it is converted to 13 5-HIAA before it reaches the cerebrospinal fluid. 14 Q. All right. What if the neuron was acting 15 normally in the storage of the serotonin, the storage bodies 16 were acting normally, and all the autoreceptors and other 17 receptors that regulate the input of serotonin into the 18 synaptic cleft were working normally and you added fluoxetine 19 where you prevented the reuptake of serotonin, what would 20 occur in that instance? 21 A. I think there would be an increased amount of 22 serotonin in the synaptic cleft, which would then begin to 23 activate the autoreceptor as well as the postsynaptic 24 receptor, and this activation would then begin to slow down 25 the amount of serotonin released and limit the extent to which 83 1 this increase was occurring out there and limit the extent to 2 which neurotransmission was then occurring. 3 Q. All right. Is there any way to know by any 4 independent test or diagnostic procedure whether or not an 5 individual's serotonin system as we have described it is 6 actually working correctly or incorrectly? 7 A. There are procedures that people are using in an 8 attempt to learn that. The extent to which that is possible 9 is -- let's say it ought to become possible to do that more 10 confidently in the future. 11 Q. Do you know of anybody at Eli Lilly and Company 12 that's working on that? 13 A. You're specifically still referring to studies 14 in humans? 15 Q. Yeah. 16 A. No. I don't know of anyone. 17 Q. Is anybody at Eli Lilly and Company working on 18 that with respect to animals? 19 A. Yes. Certainly in a broad sense. 20 Q. What is down regulation? 21 A. Down regulation is a term that is ordinarily 22 used to mean changes in some constituent of a biological 23 system such as a receptor, which occurs in response to some 24 prolonged alteration or perturbation of that system. 25 Q. Is it correct that in your early studies on 84 1 fluoxetine and animals that you found a down regulation in the 2 serotonin receptors? 3 A. When you refer to your studies, are you asking 4 about studies in my laboratory or studies at Eli Lilly and 5 Company in general? 6 Q. At Eli Lilly and Company in general? 7 A. Yes. There were such studies that were 8 conducted that examined changes in serotonin receptors as 9 measured by radioligand binding. 10 Q. All right. And what's the implication of down 11 regulation, Doctor Fuller? 12 A. In general, when receptors are exposed to an 13 increased amount of transmitter, it would not be unusual for 14 them to down-regulate, and if they are exposed to a reduced 15 amount of neurotransmitter, it would not be unusual for them 16 to up-regulate. 17 Q. Were there ever any studies done that 18 demonstrated receptors up-regulating in response to an 19 inadequate source of serotonin? 20 A. Studies by whom? 21 Q. Anybody. 22 A. Anybody? Yes. There have been such studies. 23 Q. Doctor Wong said that in down regulation, I 24 believe it was 25 to 30 percent of the effectiveness of the 25 receptor site is reduced. Does that conform with your 85 1 understanding? 2 A. You would have to tell me what the meaning of 3 the word "effectiveness" was there. 4 Q. Well, it's my recollection we were in a 5 discussion about whether or not that receptor site, by virtue 6 of shutting down or down regulating, whether it becomes 7 inactive or totally inoperable. And I think his response was, 8 well, whatever it does, it becomes 25 to 30 percent less able 9 to receive the excess serotonin. 10 A. Since I didn't hear that conversation I couldn't 11 say anything relative to it, but I could comment in general on 12 what down regulation means in terms of function. 13 Q. All right. 14 A. In general, what one is measuring in these 15 studies is the actual number of receptor sites and there is -- 16 there might be, for example, a 25-percent reduction in the 17 number of receptor sites. 18 Q. Does that mean they're just gone? 19 A. At that time, yes. 20 Q. Forever? 21 A. No. 22 Q. Okay. 23 A. Receptors are dynamic things. They are 24 constantly being degraded and synthesized, but the receptors 25 that are in my brain today are not the same receptors that 86 1 were there ten years ago or even less, so that receptors are 2 constantly being formed and being degraded and being replaced. 3 When down regulation occurs, they're simply at that point in 4 time are fewer receptors than there had been at the initiation 5 of whatever event you used to cause the down regulation. That 6 is not synonymous with saying there's a 25-percent reduction 7 in function that might or might not change in parallel. 8 Q. It could -- you're saying it might or might not. 9 So you mean it could potentially result in a 25-percent loss 10 of function of neurotransmission? 11 A. The presumption would be that there would be 12 some reduction in neurotransmission and it could turn out 13 probably to be exactly the same percentage as to change in 14 receptor sites, yes. 15 Q. How long does it take for down regulation to 16 occur? 17 A. Down regulation of what, where? 18 Q. Of the serotonin system or of the receptor. 19 It's the receptors themselves that are down regulated; is it 20 not? 21 A. The question would have to pertain to a 22 particular neuron system; that is, the different serotonin 23 pathways in the brain. If you do some alteration, they may 24 not all respond the same way and they may not all respond at 25 the same rate, so that question would have to be more 87 1 specific. But, in general, I could answer by saying that 2 receptor changes of this sort, adapting changes in receptors 3 typically with neurotransmitters would occur within a few 4 weeks. 5 Q. Could it occur in a shorter time? 6 A. There may be circumstances where it occurs in a 7 shorter time, yes. 8 Q. What would be circumstances that would cause it 9 to occur in a shorter time? 10 A. There are simply some systems that may adapt in 11 a shorter time than others. I don't know that one would refer 12 to that as a cause. 13 Q. Okay. So the receptors themselves may be 14 reduced physically by as much as 25 percent in down regulating 15 to adapt to the excessive serotonin that's being produced? 16 A. That's correct. 17 Q. To not being produced to which they are being 18 exposed to? 19 A. That's correct. 20 Q. Okay. And down regulation is something that 21 occurs only at the receptor sites. It has to do with the 22 response of the receptor sites to the availability of 23 serotonin or overavailability of serotonin in the synaptic 24 cleft? 25 A. Well, down regulation can occur because there 88 1 has been a change in the number of receptors or because there 2 has been a change in the function of the receptor. 3 Theoretically, there can be at least those two different 4 mechanisms by which a process that would be called down 5 regulation might occur. 6 Q. But down regulation isn't -- 7 A. It is ordinarily used to mean a change in 8 receptors as opposed to something else. 9 Q. And the receptors can be reduced -- receptor 10 sites, at least, can be reduced by 25 to 30 percent, is that 11 correct, in a down regulation? 12 A. Well, what receptors are you referring to? 13 Q. Those receptors of serotonin on the postsynaptic 14 neurons and the autoreceptors in the presynaptic neurons or in 15 other locations on the neurons. 16 A. I don't understand the point you're making by 17 putting a limit on the extent to which that might occur. In 18 theory, it could occur outside those limits. 19 Q. All right. And the neurotransmission occurs 20 only at the receptor sites? 21 A. The receptor is an integral part of 22 neurotransmission, yes. 23 Q. The message from serotonin won't go from the 24 synaptic cleft into the postsynaptic neuron unless it goes via 25 the receptor? 89 1 A. That's right. 2 Q. And how long will these receptors remain in a 3 down-regulated state? 4 A. In what conditions, under what circumstances? 5 Q. In any circumstances in which they're in a 6 down-regulated state, how long will they remain in a 7 down-regulated state? 8 A. If they're down-regulated because there's an 9 excess of serotonin, I would assume they would remain 10 down-regulated for as long as that excess serotonin persists, 11 however long that is. 12 Q. All right. And could there be a situation where 13 there is an excess serotonin activity indefinitely? 14 A. Could there be? I suppose. 15 MR. SMITH: At this time, Your Honor, we have an 16 exhibit to offer. 17 JUDGE POTTER: Okay. 18 MR. SMITH: It is Plaintiffs' Exhibit 32, also 19 the same as Fuller Exhibit 2. 20 SHERIFF CECIL: (Hands exhibit out to Jurors). 21 JUDGE POTTER: Ladies and gentlemen -- I'll wait 22 till my sheriff gets through passing those out. Okay. Ladies 23 and gentlemen, I think this is the first time you've seen a 24 document with the word confidential or something else written 25 on it, so I want to instruct you as follows: During the 90 1 course of the trial, the parties may use or introduce into 2 evidence certain documents and enlargements and transparencies 3 of documents which have on them a legend or stamp indicating 4 the document is confidential. In regard to this confidential 5 stamp or legend, the Court instructs you that the exchange of 6 documents in the parties in this case have been governed by 7 various court orders which provide for the making or marking 8 of documents as confidential. In the making of this case, the 9 Court instructs you that you should not draw any inference or 10 reach any conclusion one way or the other based on the fact 11 that the document has been stamped or marked confidential. Do 12 you-all understand what I'm saying? 13 Go ahead, Mr. Smith. 14 Q. Doctor Fuller, I've handed you a document marked 15 as Fuller Exhibit 2, which appears to be potentially a chapter 16 in a book that was authored by you. Can you review it and see 17 if you can identiry what Exhibit 2 is? And I'll tell you, 18 Doctor, going in, that the documents that I'm going to show 19 you are documents that have come from your file. That 20 confidential legend is stamped across each and every page, was 21 stamped by somebody in the legal staff at Eli Lilly and 22 Company, so this is from your file and may give you assistance 23 in identifying this document. 24 A. I don't think I need assistance, but I need a 25 reminder of what exactly the question was. 91 1 Q. Can you identify what's been marked as 2 Exhibit 2? 3 A. Yes. It's something that I wrote. 4 Q. Is it a chapter in a book? 5 A. I believe that's right. 6 Q. I can't tell from looking. Do you recall what 7 book this is from? 8 A. Probably is from Progress in Drug Research. 9 Q. I'm sorry? 10 A. I think it may be from Progress in Drug 11 Research. 12 Q. That's the name of a book; is that right? 13 A. That's right. 14 Q. When was that book published? 15 A. I couldn't tell you that from memory, within the 16 past ten years. 17 Q. Do you recall writing the article? 18 A. Yes. 19 Q. Would you turn with me to Page 2 of the exhibit, 20 which would be Page 86, to the second paragraph, Science and 21 Drug Action. Do you see that? 22 A. Yes, I do. 23 Q. You say there in about -- I believe it's the 24 third paragraph of Page 2 of Paragraph 2, third sentence, it 25 says serotonin -- quote, serotonin is stored in granules or 92 1 vesicles from which it is released at nerve impulse into the 2 synaptic cleft, end quote; is that correct? 3 A. Yes. That is correct. 4 Q. Is it -- does that sentence mean when we look at 5 exhibit -- well, let's mark this as an exhibit so we can talk 6 about it. And I believe, Your Honor, that's the exhibit that 7 the jury has. 8 Question: When we look at Exhibit 3, which is 9 your drawing, that a nerve impulse has to come down this 10 neuron to kick or to cause the release of serotonin from the 11 storage granule -- from the storage granule or vesicle? 12 A. Yes. 13 Q. It's not the autoreceptors that cause the 14 release, then, it's the nerve impulse? 15 A. That's correct. 16 Q. Is the nerve impulse, as you're describing it, 17 that travels along the neuron, a charge of electrical energy 18 or is that a chemical? 19 A. No. It's an electrical impulse, yes. 20 Q. What causes that electrical impulse? 21 A. Some signal to the neuron from another neuron or 22 a spontaneously programmed firing of that neuron. 23 Q. But the firing or the impulses in an electrical 24 firing or an electrical impulse? 25 A. Yes. 93 1 Q. Which is movement of energy; correct? Is that 2 correct? 3 A. I think electricity is a movement of electrons, 4 principally. 5 Q. Which is energy? 6 A. No, I don't think so. 7 Q. Movement of electrons is not energy? 8 A. Electrons is not energy. It's an electrical 9 impulse. I'm not sure either of us are electricians. 10 Q. Is that electrical impulse generated by a 11 chemical reaction? 12 A. It would certainly involve chemical changes. 13 Q. And does involve? 14 A. Yes. 15 Q. And can you tell us as an expert in biochemistry 16 that this movement of electrons that you mentioned in these 17 neurons is caused by a chemical reaction or change? 18 A. I would say it involves a chemical reaction. 19 Q. I'm just not clear, Doctor Fuller. I thought 20 earlier that the autoreceptors to some extent or did cause 21 this release of serotonin from the serotonin granule or 22 vesicles, but from what I read from this book that you 23 authored that the nerve impulse causes it to be released into 24 the synaptic cleft? 25 A. What I explained earlier was that the 94 1 autoreceptors can modulate or influence the amount of 2 serotonin that is released from the synaptic cleft. I think I 3 emphasized once or twice the autoreceptors do not initiate the 4 release of serotonin. 5 Q. Okay. It may very well be that I didn't 6 understand it, but the primary impetus from the release of the 7 storage facility is the transmission of the nerve impulse 8 along the neuron; is that right? 9 A. Yes. 10 Q. You say in the last sentence on Page 86, these 11 receptors or serotonin neurons are called autoreceptors. The 12 terminal autoreceptors have the physiologic role of sensing 13 the concentration of serotonin in the synaptic cleft and 14 modulating the further release and synthesis of serotonin, end 15 quote. Is that what you were explaining just a minute ago? 16 A. Yes, it is. 17 Q. That's this autoreceptor that modulates the 18 release? 19 A. Yes. 20 Q. Does the autoreceptor have any function in the 21 reuptake or transport of serotonin from the synaptic cleft? 22 A. No, not so far as we know. 23 Q. At least as far as you can tell from a 24 scientific certainty, it doesn't have anything to do with 25 that? 95 1 A. With the transport; that's correct. 2 Q. Turn to Page 88 -- the first, I guess it would 3 be the second full paragraph. You say, "Despite the decreased 4 activity of serotonin neurons, serotonergic neurotransmission 5 is enhanced after uptake in inhibition leading to behavioral 6 and other changes, especially when uptake inhibitors are 7 combined with serotonin precursors; correct? 8 A. Yes. 9 Q. Now, on Page 91, the last paragraph, you state 10 there is no reason to believe that our understanding of 11 serotonin receptor subtypes is complete at this time and 12 already evidenced for additional subtypes of serotonin 13 receptors is building; is that correct? 14 A. That is correct. 15 Q. I guess what I don't understand is do the 16 different kind of receptors act differently or receive 17 different types of serotonin messages? 18 A. For example, they may differ in the 19 concentration of serotonin that is required to activate them. 20 Some of them might be activated by smaller concentrations of 21 serotonin than others. They might be present in different 22 parts of the brain. In one serotonin pathway, for example, 23 there might be 5-HT-1A receptors and in another pathway there 24 might be 5-HT-1C receptors or something of that sort, but they 25 are all responding to serotonin. 96 1 MR. SMITH: Your Honor, at this time, we would 2 offer Exhibit 4. 3 JUDGE POTTER: Which is No. 34. 4 MR. SMITH: Yes, it's Plaintiffs' Exhibit 34. 5 MR. SMITH: Would you like one? 6 MS. ZETTLER: Please. Thank you. 7 SHERIFF CECIL: (Hands exhibit to Jurors). 8 Q. Can you identify Exhibit 4, Doctor Fuller? 9 A. Yes. 10 Q. It appears to be a paper that you wrote more 11 recently in 1991, along with Doctor Fuller and Doctor 12 Robertson. I mean, along with Doctor Wong and Doctor 13 Robertson. 14 A. That's right. 15 Q. Now, if you will turn with me to Page 24, to the 16 last sentence of Page 24, it says, "When fluoxetine is 17 administered to animals, the serotonin uptake inhibition that 18 results initially is caused by fluoxetine itself. With time, 19 fluoxetine is converted to norfluoxetine and the long duration 20 of serotonin uptake inhibition following a single dose of 21 fluoxetine is due at later times to the formation and 22 persistence of norfluoxetine;" is that correct? 23 A. Yes. That is correct. 24 Q. Possibly you should explain that to us in 25 connection with your diagram, the fact that norfluoxetine 97 1 comes into play somehow. 2 A. Well, I'm not sure that the diagram is very 3 helpful explaining that. The situation is that when 4 fluoxetine is given to an animal or to a human, it is 5 metabolized by a process referred to as N-demethylation, which 6 is described in more detail in this paper, the product being 7 the compound that we called norfluoxetine. It is simply 8 fluoxetine with the methyl group removed from the nitrogen in 9 the molecule, and that product norfluoxetine is virtually 10 identical to fluoxetine in its ability to block serotonin 11 uptake and in its selectivity in blocking serotonin uptake; 12 that is, it also doesn't block norepinephrine uptake and also 13 doesn't interact with these receptors we've talked about. So 14 that when one gives fluoxetine to a rat, for example, 15 serotonin uptake is inhibited, as I mentioned earlier, for 24 16 hours or more. And if one measured what is in the brain 17 during that time, what you find at the early time, like one 18 hour, is that what is in the brain is mostly fluoxetine but, 19 with time, the amount of fluoxetine keeps decreasing and the 20 amount of norfluoxetine increases over a period of time. So 21 at 24 hours, when uptake is still inhibited, what is present 22 in the brain is mostly norfluoxetine, so that the uptake 23 inhibition at 24 hours is being produced by the metabolite 24 rather than by serotonin, by fluoxetine itself. 25 The action is the same; it's just that at early 98 1 times it's being exerted by the parent drug and at later times 2 it's being exerted by the metabolite, principally. 3 Q. Turn with me to Page 28, beginning with the last 4 one and a half words on that page. It says, "The decreased 5 turnover of brain serotonin after fluoxetine administration is 6 thought to be due to increased activation of autoreceptors on 7 serotonin neurons whose physiologic role in sensing the 8 extraneuronal concentrations of serotonin and modulating the 9 further release and synthesis of serotonin." Do you see that? 10 A. I'm sorry, the question? 11 Q. Did you -- have you got that? 12 A. Yes. I see that. 13 Q. Now, is that down regulation or is that turnover 14 that you're talking about or neither? 15 A. It's not down regulation, it's -- yes. The 16 synthesis and utilization of serotonin is decreased so that's 17 turnover. The turnover the serotonin is decreased. 18 Q. Now, turn with me to Page 30. In the first 19 paragraph under Therapeutic Effects of Fluoxetine in Humans, 20 you say uptake inhibition would be expected to enhance 21 serotonergic input to the postsynaptic neurons in many brain 22 regions to which serotonergic terminals project, and it is not 23 possible to know at present which brain regions or which 24 postsynaptic neurons are most important in leading to 25 therapeutic effects in depression; is that correct? 99 1 A. Therapeutic effects in depression? 2 Q. Right. 3 A. That's correct. 4 Q. Explain that to me. Are you saying that there's 5 some neurons that may be more important in regulating mood or 6 depression than others? 7 A. Yes. That's correct. 8 Q. And would these be serotonin-producing neurons 9 exclusively? 10 A. No. This is referring to postsynaptic neurons 11 so that -- serotonin neurons are very widely distributed in 12 the brain and those kinds of synaptic connections are present 13 in many different parts of the brain that are concerned with a 14 lot of different things the brain controls, feeding, for 15 example, as we've talked about, certain endocrine functions 16 and so on. And there are, no doubt, particular parts of the 17 brain where these pathways are what has accounted for the 18 antidepressant activity of serotonin uptake inhibitors. And 19 where exactly in the brain those pathways are and what the 20 postsynaptic neurons are is what is the center of this 21 discussion. As pointed out at this point, there's not a lot 22 known about that. 23 Q. Doctor Fuller, as I understand it, both 24 fluoxetine and norfluoxetine as metabolite act only at the 25 transport site? 100 1 A. That's right. 2 Q. Now, do fluoxetine and norfluoxetine compete 3 there at the transport site? 4 A. Do they compete with serotonin? 5 Q. Yeah. 6 A. Yes. 7 Q. Do they compete with each other for locations at 8 the transport site? 9 A. I would assume so, yes. 10 Q. Have there been any studies done to determine 11 the rate at which they compete with each other? 12 A. The rate at which they compete with each other. 13 I'm not sure I understand the use of the word "rate." 14 Q. Or the manner in which? 15 A. The extent to which they compete with each 16 other? 17 Q. Yeah. 18 A. Well, I guess the closest -- I don't think 19 that's an issue that has been addressed or that is 20 particularly relevant, to be honest, but the closest I can 21 think of experimentally that experiments have been done that 22 would address that would be the use of radioactive fluoxetine 23 as a radioligand to label that transporter site, and then the 24 addition of nonradioactive fluoxetine to see the extent to 25 which it competes with that radioligand binding and, yes, 101 1 those experiments have been done. 2 Q. And what were the results? 3 A. The results were exactly as expected, that is, 4 they both have a high affinity for that serotonin transport. 5 Q. And this may be way too crude, but let's assume 6 that we have a serotonin transport site upon which fluoxetine 7 and norfluoxetine work and there is -- and they compete for 8 serotonin at that site; correct? 9 A. Yes. 10 Q. And let's say that there are six possible 11 locations for one of those molecules to sit at that transport 12 site. All right? 13 A. Okay. 14 Q. I think we've established or you have explained 15 to us that initially what you have is you have fluoxetine that 16 comes in and takes up those sites; correct? 17 A. Yes. 18 Q. And serotonin is not able to get at one of those 19 sites at the table; is that right? 20 A. Yes. That is right. 21 Q. And by virtue of that, the transport of 22 serotonin is blocked at the transport site? 23 A. That's right. 24 Q. Would it be reasonable -- would it be a 25 reasonable scientific assumption that in the majority of 102 1 humans taking fluoxetine that the serotonin at some or many 2 sites, the transport sites of serotonin are totally occupied 3 by fluoxetine? 4 A. It's a possibility. 5 Q. Is there a difference in the half-life between 6 fluoxetine and norfluoxetine? 7 A. By half-life you're referring to the time it 8 takes for the levels in some place such as plasma or brain to 9 disappear? 10 Q. Yes. 11 A. Yes, there is a difference. 12 Q. What is that difference? 13 A. Well, what place are you talking about? 14 Q. Brain tissue. 15 A. Of what species? 16 Q. Humans. 17 A. I have no idea. 18 Q. Rats? 19 A. Rats, I don't have the half-lives memorized, but 20 it's obviously roughly -- I don't know, a few hours for 21 fluoxetine and several hours for norfluoxetine. I imagine 22 those numbers have been calculated in some publications, but 23 they aren't particularly useful to me. 24 Q. I seem to recall literature to the effect that 25 if fluoxetine or norfluoxetine has a longer half-life than 103 1 other antidepressants and there's cautions about administering 2 other medications quickly after discontinuing fluoxetine by 3 virtue of the long half-life of fluoxetine or norfluoxetine, 4 which means that it continues to be present in an individual 5 system for a period of time after discontinuance of 6 administration of the drug. Do you recall literature to that 7 effect? 8 A. You're referring now to clinical literature, 9 yes. 10 Q. All right. And that's what I'm speaking of when 11 I'm talking about long half-life. Is norfluoxetine -- is it 12 norfluoxetine that has a long half-life or fluoxetine? 13 A. Norfluoxetine. Plasma half-lives in humans are 14 longer for norfluoxetine than they are for fluoxetine. 15 Q. Can you quantify that? 16 A. No. I don't remember those numbers, but it's 17 several days for norfluoxetine and it's a shorter time for 18 fluoxetine. 19 Q. And you don't know what they are in the brains 20 of humans? 21 A. In human brains, how would you determine that? 22 Q. I don't know. You're the expert, Doctor. I'm 23 asking whether or not somebody can tell that, tell what the 24 half-life of fluoxetine is in the human brain. 25 A. The question is, is there a way of determining 104 1 fluoxetine in human brains? 2 Q. The half-life in the human brain. You just gave 3 us kind of a description of the half-life in plasma. 4 A. There's no way to obtain human brain tissue for 5 a study like that short of autopsy samples or something of 6 that sort, which wouldn't be a way that such information 7 should be obtained, I don't think. Plasma half-life is what 8 one measures in humans. 9 Q. And the plasma half-life of fluoxetine and 10 norfluoxetine in humans is similar to at least the comparative 11 half-lives you described for us in rat brains? 12 A. No. They're longer. The half-lives are longer 13 in human plasma than rat plasma. 14 Q. Both half-lives? 15 A. Both half-lives. 16 Q. How about the comparitor? 17 A. In both species the half-life of norfluoxetine 18 is longer than the half-life of fluoxetine. 19 MR. SMITH: At this time, Your Honor, we have 20 exhibit -- Plaintiff's Exhibit 35, which was Fuller Exhibit 6 21 in his deposition. 22 JUDGE POTTER: Okay. Thank you. 23 SHERIFF CECIL: (Hands exhibit to Jurors). 24 Q. All right. Read for me Exhibit 6. Have you 25 read it? 105 1 A. Yes, I have. 2 Q. Do you recall authoring Exhibit 6? 3 A. Yes, I do. 4 Q. Doctor Fuller, what were the 5 circumstances that caused you to write Exhibit 6? 6 A. Well, I would judge it to be a telephone 7 conversation I had with a Newsweek reporter. 8 Q. And did the Newsweek reporter bring up the 9 subject of down regulation and serotonin production? 10 A. That is what this memo says, yes. 11 Q. Do you recall specifically speaking with the 12 reporter? 13 A. No, other than through the help of this memo, 14 no. 15 Q. Do you recall why you directed this memo to the 16 individuals mentioned in this group up on the top left-hand 17 side of the page under the April 4th date? 18 A. It no doubt has to do with the explanation in 19 the first paragraph that this is a type of misunderstanding 20 that I expected we will hear again, even though I didn't spell 21 "hear" right, and therefore I was addressing it to those 22 people I thought most likely to hear those things. 23 Q. Do you think that you have adequately summarized 24 what your opinions are in connection with down regulations and 25 the misunderstandings that have been left with respect to down 106 1 regulations in this memo? 2 A. I would hope it would be adequate, yes. 3 Q. Is down regulation in the context of serotonin 4 and neurotransmission a scientific term? 5 A. The term down regulation, as I have heard it 6 used by neuropharmacologists and psychopharmacologists in 7 relationship to serotonin neurotransmission, has referred to 8 adaptive changes in receptors for serotonin, and that is not 9 the term that is used here. 10 Q. You're saying that the misunderstanding is 11 people are using down regulation in describing 12 neurotransmission along the neurons in general and that that 13 shouldn't be used; is that correct? 14 A. No. That is not correct. 15 Q. Okay. Then tell me what is accurate in 16 connection -- 17 A. If you look at Exhibit 6, the third line uses 18 the phrase "down regulation of serotonin production." That is 19 the term that I've just said is not one that is used by 20 knowledgeable neuropharmacologists. 21 Q. Well, is serotonin production reduced in the 22 presynaptic neuron in the presence of fluoxetine? 23 A. Yes. I explained that in considerable detail 24 earlier. 25 Q. All right. But that doesn't have anything to do 107 1 with the actual transmission of the impulse; is that what 2 you're saying? 3 A. No. That is not what I'm saying. 4 Q. Okay. I just want to be clear, Doctor, and I 5 know it's late and I'm not trying to beat a subject to death; 6 I'm just trying to get it straight. Please bear with me a 7 little longer. 8 A. I don't mind explaining it once again, if you 9 would like. 10 Q. Let's try it once again. 11 A. When uptake is inhibited and serotonin increases 12 in the synaptic cleft, there is increased activation not only 13 of the postsynaptic receptors but also of the presynaptic 14 autoreceptors so that the amount of serotonin that is being 15 made and released is diminished. Those changes occur because 16 of the increased amount of serotonin in the synaptic cleft, so 17 they do not mean that serotonin neurotransmission is 18 decreased. They are occurring because there is more serotonin 19 here in this synaptic cleft and therefore there is more 20 activation of the postsynaptic changes. Those are acute 21 changes that occur within minutes after giving an uptake 22 inhibitor to an animal, let's say, where we can measure these 23 things. So what I'm talking about is based on studies in 24 animals, essentially. 25 Over time, with repeated administration of an 108 1 uptake inhibitor, this increased amount of serotonin in the 2 synaptic cleft can lead to a second type of adaptive response, 3 which is a down regulation of receptors. And that can occur 4 apparently both with some, but not all, postsynaptic receptors 5 and some presynaptic receptors. Through all of this, so far 6 as we can tell, serotonin neurotransmission is increased after 7 uptake inhibition. It's not increased as much as it would 8 have been if those adaptive changes had not occurred, but they 9 are occurring because there is more serotonin there in the 10 synaptic cleft so there's more neurotransmission, and that, in 11 essence, is the situation as I understand it. 12 Q. Is there ever a point where down regulation 13 renders a receptor unable to be activated? 14 A. Well, as I explained earlier, there are at least 15 two different types of down regulation that can occur; one is 16 a reduction in the receptor number and the other would be a 17 reduction in a receptor efficiency. So far as I know and can 18 remember, all of the decreases in serotonin receptors that 19 have been reported -- and let me emphasize that it's probably 20 only serotonin receptors labeled with titrated serotonin that 21 have been shown to undergo this kind of down regulation. So 22 far as I know, that has been a decrease in receptor number. I 23 don't recall any example of where there was a decrease in 24 receptor sensitivity or efficacy, so that obviously those 25 receptors that are not there anymore will not be active, but 109 1 those receptors that are still there will be as active as they 2 were before. And since there is an increased amount of 3 serotonin out there, the overall result is an increase in the 4 amount of neurotransmission but a somewhat small increase than 5 would have occurred if those receptors had not been 6 down-regulated. 7 Q. What if you removed the fluoxetine and they're 8 down regulated, either gone completely or functionally less? 9 A. Then the answer would be back to normal. 10 Q. Do you know that for a fact? 11 A. Do I know that for a fact? As well as I know 12 the other things for a fact. 13 Q. Have there been tests that have shown that the 14 down regulation or the function of the receptors that are 15 still there goes back to normal? 16 A. You mean that the changes in receptors have been 17 shown don't last forever? 18 Q. Right. 19 A. I think that's been shown. I'm not aware of any 20 example in all of pharmacology where adaptive changes in 21 receptors like that have been shown to persist longer than the 22 stimulus that caused them. 23 Q. What about the ones that are no longer there? 24 A. Again -- 25 Q. You said earlier -- you implied that they -- 110 1 A. It's a dynamic thing. Every receptor that's 2 there wasn't there sometime back and won't be there sometime 3 in the future. There's a dynamic -- I can't say it so I won't 4 use it, but there's a dynamic nature to these receptors. 5 They're always undergoing turnover. 6 Q. Okay. How long does it take to turn over? 7 A. I don't know the answer to that. I don't know 8 that that's been determined with these serotonin receptors. 9 Q. Has anybody tried to determine that? 10 A. Probably, but not that I specifically remember. 11 Q. Do you know if anybody has tried and failed? 12 A. No. I simply don't remember. 13 Q. Have you tried to determine that? 14 A. No. 15 Q. Why not? 16 A. Well, that's not the type of experiments that I 17 do. I don't do radiologic receptors, which would be one way 18 of trying to approach that. It's not a question that would 19 help me in my research particularly. 20 Q. Let's talk about a situation where the number of 21 receptors decreases. Okay? 22 A. Yes. 23 Q. I'm limiting it to the one circumstance where 24 the number decreases; I'm not talking about the level of 25 functioning decreasing. Okay? I'm just trying to get it 111 1 clear what you mean when you say the actual number of 2 receptors decrease. Are you talking about, for instance, as 3 an analogy, ten receptors on a neuron and then all of a sudden 4 there's only six as a result of down regulation? 5 A. A decrease in the number of receptors. What I 6 mean is that there are fewer receptors at the site as a result 7 of some treatment than there had been before that treatment. 8 Q. Okay. So some of the receptors go away as a 9 result of the treatment in that circumstance? 10 A. That's not the equivalent to what I said, no. 11 Q. Where am I getting it wrong, Doctor? 12 A. There are two -- at least two general ways in 13 which the number of receptors would go down. 14 Q. Okay. 15 A. One is that receptors are disappearing at a 16 faster rate than they had been disappearing, and the second is 17 receptors are being made at a slower rate than they had been 18 being made. 19 Q. So as a result of down regulation or 20 down-regulated adaptive change in this instance, where there 21 are less receptors, it can either be because they are 22 disappearing at a faster rate or being made at a slower rate? 23 A. Yes. 24 Q. Okay. Which part don't -- I mean, is the down 25 regulation affecting neurotransmission, as far as you can 112 1 tell, in animals that are administered fluoxetine? 2 A. I can tell you what I would expect. May we do 3 that? 4 Q. Sure. 5 A. What I would expect is exactly as I said 6 earlier, I think, that as a result of the increased amount of 7 serotonin that is in the synaptic cleft, there are at least 8 two different kinds of adaptive changes that have been shown 9 to occur. The most rapid one is a reduction in the rate at 10 which serotonin is being made and released and that limits the 11 extent to which serotonin increases here. 12 Q. That's called turnover? 13 A. That could be called -- 14 Q. Decreased turnover? 15 A. Thats could be called decreased turnover, yes. 16 I think it's more informative to say a decrease in the amount 17 of serotonin that has been made and released, but if you would 18 prefer turnover I would allow you to use that. There's been a 19 later adaptive change in certain serotonin receptors, and 20 apparently not all of them, which again limits the extent to 21 which neurotransmission is increased. There is no 22 hypothetical basis that I can think of and no experimental 23 data that I know of that would suggest neurotransmission is 24 not increased during all of this but, rather, these adaptive 25 changes place limits to the extent to which that increase 113 1 occurs. 2 Q. I guess my question then is, how do you know 3 that neurotransmission increases? 4 A. By virtue of many of the measurements that were 5 referred to in earlier memos and that I have referred to in 6 numerous publications, such as Exhibit 4, the Section 7 7 entitled Functional Effects of Fluoxetine In Vivo, and Section 8 8, entitled Therapeutic Effects of Fluoxetine in Humans. 9 Q. One of those effects is fluoxetine reducing 10 rapid-eye-movement sleep in rats and cats? 11 A. Yes. 12 Q. There are a number of virtually -- let's start 13 back again. 14 Okay. How is it that you know that fluoxetine 15 reduces rapid-eye-movement sleep in rats then? 16 A. How is it that I know that? 17 Q. Right. Because they simply gave it to the rats 18 and their REM sleep was reduced? 19 A. Yes. Yes. 20 Q. I just want to know if other than the fact that 21 it was noted that in rats, once fluoxetine was administered 22 their REM sleep decreased, other than that fact, was there 23 anything else that was done to determine whether or not 24 fluoxetine did cause that effect of neurotransmission is 25 affected and how that effect reduces the REM sleep. In other 114 1 words, you can't sit there and look at a neuron and watch a 2 neuron act, can you? When you sit there, can you watch a 3 neuron in action? Can you watch an actual neurotransmission 4 as it occurs, I mean, a specific neurotransmission on a 5 specific neuron? 6 A. Can you watch it occurring? 7 Q. Can you actually see it with the naked eye with 8 a microscope? 9 A. You cannot see a neuron with the naked eye. 10 Q. Can you see it with a microscope? 11 A. Yes. 12 Q. Okay. Have you ever watched a neurotransmission 13 of a serotonin neuron after it's been administered fluoxetine 14 or fluoxetine -- 15 A. Through a microscope? 16 Q. Right. 17 A. No. 18 Q. Why not? 19 A. It isn't possible to do that through a 20 microscope. You can see neurons through a microscope but you 21 can't see neurons in the intact brain of a living animal 22 through a microscope. 23 Q. Okay. Can you see neurons in the intact brain 24 of a living human through that microscope? 25 A. No. 115 1 Q. Isn't this really what is called a putative 2 drug? 3 A. A putative drug? 4 Q. Right. A putative theory. 5 A. I think it's a real drug. 6 Q. Okay. Is its effects on depression putative? 7 A. I think they're real effects. They have been 8 observed by many people. 9 Q. Do you know of any study done by anyone at any 10 time that indicates how long those receptors -- serotonin 11 receptors remain in a down-regulated state? 12 A. I have read probably most of the publications on 13 that subject, but which of those studies actually investigated 14 how long the effect occurred, I could not tell you from 15 memory. 16 Q. Are there any studies that examine how long the 17 effect of down regulation occurred? 18 A. I think that it must be apparent from my 19 previous answer that I couldn't tell you that from memory. 20 Q. Well, it wasn't to me. So you don't know -- so 21 we'll make sure the record is straight, Doctor Fuller, you 22 don't know whether or not there have been any studies to 23 determine how long those receptors that are down-regulated 24 remain in down-regulated state; is that correct? 25 A. As I mentioned, if this is described in the 116 1 publications that I have read, then I certainly knew that at 2 one time, but I do not remember it at this moment. 3 Q. Well, are you saying you think there are some 4 studies that address that issue? 5 A. I'm saying there are some studies which may 6 address that issue and which I don't remember in sufficient 7 detail at the moment to tell you whether they do or don't 8 address that particular issue. 9 Q. Well, do you know of any studies where research 10 animals, that is, rodents, rats or mice, were administered 11 fluoxetine and then for a period of time -- then the 12 fluoxetine was discontinued, then after a period of time the 13 rats were sacrificed or the experimental animal, whatever, was 14 sacrificed and there was some study to determine whether or 15 not there was any evidence of any injury or long-term effects 16 of the down regulation which had occurred in the receptors of 17 that particular research animal? 18 A. I think the studies we have been talking about 19 are the studies of the general type that you described where 20 fluoxetine is given to a test animal for a period of time and 21 then discontinued. And in some such studies there have been 22 an examination of receptors for serotonin labeled with some 23 appropriate radioligand that have suggested there is a down 24 regulation of those receptors; that is, a reduced number of 25 certain receptors, and in some studies there has been the 117 1 finding that there is no down regulation of those receptors. 2 And in those studies where there was a down regulation of 3 receptors, to my knowledge there would never be any 4 expectation that that would result in injury and no evidence 5 of any sort that there was any injurious consequence of that 6 adaptive change. 7 Q. Well, has anyone done a study to determine how 8 long this down regulation of these receptor sites continues? 9 A. The answer which I gave earlier is that there 10 have been some published studies on the matter of whether 11 adaptive changes in receptors occur in animals after repeated 12 administration of fluoxetine, and in some such studies there 13 were changes found in receptors -- serotonin receptors and in 14 some studies there were not. In those studies which there 15 were changes found, I do not recall without referring to those 16 papers whether the duration of those changes was measured. 17 Q. As we sit here today, would that hold any 18 interest -- would that be of any interest in connection with 19 your work on fluoxetine? 20 A. In connection with my work on fluoxetine I don't 21 see where that would be of any value to know that. 22 Q. Why would it not be of any value to know that? 23 A. Because none of the research that I have done on 24 fluoxetine has concerned the down regulation of receptors at 25 all, except for a limited study which I mentioned earlier 118 1 where the phenomenon that we were measuring indicated there 2 was no adaptive changes after repeated administration of 3 fluoxetine in those receptors which mediated those effects. 4 Q. Do you remember receiving preliminary data that 5 was inconclusive, at least concerning whether or not 6 fluoxetine would be efficacious for treatment of depression? 7 A. Yes. 8 Q. All of the data prior to the double-blind 9 clinical trials were, by their nature, inconclusive? 10 A. I think that was my line. 11 Q. Excuse me. Why don't you read it. Let me ask 12 the question again. 13 A. Okay. 14 Q. Well, no, you read the answer again. 15 A. All of the data prior to the double-blind 16 clinical trials were, by their nature, inconclusive. 17 Q. Your work was inconclusive then up to that 18 point? 19 A. I did not do any work related to the clinical 20 efficacy of fluoxetine and depression. The work we were 21 discussing here is clinical studies that were done to 22 ascertain whether fluoxetine was effective in the treatment of 23 depression in humans. 24 Q. Do you believe that the work you did, the 25 experiments you did, were in any way relevant to whether or 119 1 not fluoxetine would be efficacious as an antidepressant in 2 humans? 3 A. The work I did -- that I did in animals was 4 certainly relevant, in my opinion, to the potential usefulness 5 of fluoxetine in the treatment of depression. In order to 6 find out if fluoxetine or any other drug is effective in human 7 beings who are afflicted with depression, studies have to be 8 done in humans who are afflicted with depression to find out 9 if the drug alleviates their symptoms. I did not do any such 10 research personally. 11 Q. What do you feel was the contents of your 12 studies that were relevant to the issue of whether or not 13 fluoxetine would be efficacious as an antidepressant in 14 humans? 15 A. You're referring to studies that I did as an 16 individual? 17 Q. Yes. 18 A. Not studies that Lilly did; is that correct? 19 Q. Yes. 20 A. The studies that I did were concerned with 21 showing that fluoxetine was effective in blocking the neuronal 22 uptake of serotonin and that it was selective in that regard 23 and that it was orally effective and had an adequate duration 24 of action, and that as a consequence of that block of 25 serotonin uptake, that serotonergic function was increased and 120 1 that work, when viewed in the context of the understanding at 2 that time of the role of serotonin in depression and in the 3 action of antidepressant drugs, led to the prediction that 4 fluoxetine would be effective in the treatment of mental 5 depression in humans. 6 Q. But the determination concerning whether or not it 7 would be efficacious in treatment in humans was left up to the 8 clinical trials in humans? 9 A. That is the way to determine if a compound is 10 effective in treating mental depression in humans. 11 Q. Did you draw a conclusion with respect to 12 whether or not fluoxetine would be efficacious in treatment of 13 humans for depression prior to the conclusion of the clinical 14 trials? 15 A. My conclusions about the effect, any effect of 16 fluoxetine are based upon data and the conclusions about is 17 the compound -- about is the compound effective in the 18 treatment of mental depression in humans was made based upon 19 date available from studies of the effect of fluoxetine on 20 mental depression in humans. 21 Q. When did you, in your opinion, receive 22 sufficient data to make that conclusion? 23 A. It was when the results became available from 24 the double-blind controlled studies comparing fluoxetine to 25 placebo in human subjects who were depressed. 121 1 Q. Do you have a recollection of seeing a specific 2 piece of data and saying, okay, we got our proof now, this is 3 what we've been looking for, now I'm certain or reasonably 4 certain from a scientific standpoint that this data supports 5 my belief up to that point that this would be an efficacious 6 treatment of depressed individuals? 7 A. Yes. When the results of that multi-centered 8 double-blind study comparing fluoxetine to placebo in 9 depressed patients became available, when those results were 10 tabulated and analyzed statistically, then it was clear that 11 the compound seemed to be effective as an antidepressant drug. 12 Q. Did you do any -- did you do anything to do, 13 Doctor Fuller -- did you have anything to do, Doctor Fuller, 14 with the decision to make fluoxetine available recently in a 15 ten milligram pulvule? 16 A. No. I don't believe I did have anything to do 17 with that. 18 Q. Do you know why the decision was made to make it 19 available in 10-milligram quantities? 20 A. I imagine it was because it was agreed there was 21 a medical need for that capsule strength. 22 Q. Doctor Fuller, is cocaine a serotonin reuptake 23 inhibitor? 24 A. Among the many things that cocaine does, one of 25 them is to inhibit serotonin uptake, although it isn't a very 122 1 potent serotonin uptake inhibitor. 2 Q. Can you answer that in a yes or no fashion? Is 3 cocaine a serotonin reuptake inhibitor? 4 A. The answer is yes. 5 Q. Is methadone a serotonin reuptake inhibitor? 6 A. The answer there is that it depends on the 7 circumstances that you are referring to. Would you tell me 8 exactly what you mean by that question? 9 Q. Where it's given to an individual in a 10 therapeutic mode, does that help? 11 A. Yes. I think it's very unlikely that at 12 therapeutic doses it's a serotonin uptake inhibitor. 13 Q. Is it a serotonin uptake inhibitor -- is 14 methadone a serotonin uptake inhibitor in higher than 15 therapeutic doses? 16 A. It probably would be. 17 Q. Have you ever heard of Joseph Wesbecker? 18 A. I've heard of someone named Wesbecker; I don't 19 remember his first name. 20 Q. How did you hear of this Wesbecker person? 21 A. The person I'm thinking about, I read in the 22 newspapers. 23 Q. What did you read about Mr. Wesbecker in the 24 newpapers? 25 A. That he killed some people and himself, I 123 1 believe. 2 Q. Have you discussed Mr. Wesbecker's actions with 3 anybody at Eli Lilly? 4 A. In all probability I have, but I don't remember 5 specific discussions. 6 Q. Why do you say in all probability you have? 7 A. Because I'm aware that there was a lot of 8 publicity surrounding the case which had to do with 9 fluoxetine. 10 Q. Have you, in your capacity as a biochemist at 11 Lilly, been asked by anybody at Lilly to do animal studies 12 that may be relevant to the issue of whether or not fluoxetine 13 causes people to become violent and aggressive? 14 A. I have not been asked by anyone to do such 15 animal studies, no. 16 Q. Have you done such studies? 17 A. No. I think none of the studies that I have 18 done would pertain specifically to aggression. 19 Q. Have you used any of the studies that you've 20 done in response to inquiries either by a governmental agency 21 such as the FDA or somebody at Lilly with regards to the 22 subject of violent, aggressive behavior and the use of 23 fluoxetine? 24 A. As best I understand your question, the answer 25 is no. 124 1 Q. Are you aware of any studies, animal studies 2 whatsoever, that were done at Lilly specifically in the 3 research center -- that researched whether or not there was a 4 connection between the use of fluoxetine and violent, 5 aggressive behavior? 6 A. Are you asking a connection between fluoxetine 7 and violent, aggressive behavior in people? 8 Q. We can start with rats or animals first. 9 A. There were studies on fluoxetine done at Lilly 10 that showed that it reduced aggressive behavior in rats. 11 Q. And were those studies conducted specifically to 12 study that phenomena or was that something that came up as 13 peripheral in another study? 14 A. No. They were studies that were done 15 specifically to investigate the effect on muricidal 16 aggression? 17 Q. Who conducted those studies? 18 A. Doctor Paul Stark. 19 Q. Do you know how many studies Doctor Stark 20 conducted? 21 A. No. I don't know about the number of separate 22 studies. Basically there was -- there were studies showing a 23 dose-dependent suppression of muricidal aggression in rats 24 threatened with fluoxetine. 25 MR. STOPHER: Treated. 125 1 A. I'm sorry. Treated with fluoxetine. 2 Q. So a dose-dependent what? 3 A. Suppression of aggressive behavior. 4 Q. The greater the dose, the more the behavior was 5 suppressed? 6 A. Yes. Up until a maximum suppression, of course. 7 Q. What would constitute maximum suppression? 8 A. No aggression. 9 Q. Okay. Are you aware of any other studies that 10 Doctor Stark did on researching aggressive behavior in rats as 11 it related to the use of fluoxetine? 12 A. No. 13 Q. Do you recall what the highest dose of 14 fluoxetine administered to the rats by Doctor Stark was? 15 A. No, I don't. 16 Q. Were those doses that were administered to the 17 rats by Doctor Stark, were they meant to be comparable to 18 doses in humans? 19 A. They were chosen to be doses that were known to 20 inhibit serotonin uptake in rats. 21 Q. Did every dose administered to the rats produce 22 a suppression of aggression? 23 A. I don't remember the answer to that. The lowest 24 doses may have been insufficient. That would be a typical 25 experiment, but I don't remember specifically about this one. 126 1 Q. Do you know if all the rats' aggressions were 2 suppressed? 3 A. Again, that would depend upon the dose of 4 fluoxetine. The bigger the dose, the more the suppression, 5 and I couldn't give you the numbers for individual groups of 6 rats. 7 Q. Okay. Was this study published? 8 A. Yes, it was. 9 Q. Do you know when it was published? 10 A. It was published in, I believe, the British 11 Journal of Psychiatry in a paper authored by Stark, Wong and 12 myself, I believe. 13 Q. British Journal of Psychiatry? 14 A. I believe that was the name of the journal. 15 Q. It wasn't the British Medical Journal, was it? 16 A. No, I don't think so. 17 Q. So it was Doctor Stark, Doctor Wong and yourself 18 that were the authors? 19 A. Yes, I think so, maybe not in that order. 20 Q. Did you participate in the study? 21 A. Not to a substantial degree. Probably in terms 22 of advising about the choice of doses, for example. The 23 publication was broader than that study. That was one of the 24 studies included in the publication. 25 Q. Do you recall what the title of the publication 127 1 was, not the journal but the article itself? 2 A. No, I'm sorry I don't. It certainly had the 3 words fluoxetine in the title. 4 Q. Do you remember when it was published, 5 approximately? 6 A. My guess would be about 1985. 7 Q. Why was Doctor Stark studying the suppression of 8 aggressive behavior in rats in the 1980s? 9 A. He actually wasn't studying in the 1980s. The 10 data were obtained prior to that time. The data were obtained 11 back in the '70s when most of the animal studies on fluoxetine 12 were conducted. That test was actually one that is sometimes 13 used in the characterization of antidepressant drugs, and so 14 that was a test that Doctor Stark was using in his laboratory 15 at that time. 16 Q. Okay. Are you aware of any behavioral studies 17 that were done at Lilly that demonstrated overt behavioral 18 changes of animals on fluoxetine? 19 A. No. I think -- well, are you asking other than 20 what we've talked about already? 21 Q. Yeah. I mean, I'm just interested to know if 22 there were behavioral changes that were noticed during the 23 behavioral studies that either weren't anticipated or weren't 24 being studied for. 25 A. None that I recall. 128 1 Q. How about hyperirritability in rats? 2 A. I don't remember any such effects. 3 MR. SMITH: Your Honor, we have Plaintiffs' 4 Exhibit 36, which was Fuller Exhibit 9 to his deposition. 5 SHERIFF CECIL: (Hands exhibit to Jurors). 6 MR. SMITH: Approach the bench, Your Honor. 7 (BENCH DISCUSSION) 8 MR. SMITH: How much further do you want me to 9 go, Your Honor? 10 JUDGE POTTER: When are you coming to a good 11 breaking point? You just let me know. 12 (BENCH DISCUSSION CONCLUDED) 13 Q. Go ahead and take a look at Exhibit 9, Doctor. 14 A. Yes. I see it. 15 Q. Do you recognize Exhibit 9? 16 A. It's a project team minutes in which the word 17 "team" is mistyped, written in 1974. 18 Q. And you were the author of this? 19 A. Yes. Typist as well, probably. 20 Q. So we can blame you for the typos, huh? The 21 second paragraph on the first page talks about a 90-day 22 toxicity study in rats? 23 A. Yes. 24 Q. Are you familiar with that study? 25 A. Familiar with it would certainly be an 129 1 exaggeration. I'm aware it was done, yes. 2 Q. Do you know who performed that study? 3 A. It would have been done in the toxicology 4 division at Greenfield and Doctor John Wold was the 5 toxicologist representative on the project team, although the 6 study was not necessarily done in his personal laboratory. 7 Q. Did Doctor Wold report the results of the study 8 or at least the status of the study as of the date of this 9 project team meeting? 10 A. Yes. 11 Q. And he reported that there was a pronounced 12 hyperirritability in rats, at least the class of rats that 13 were included in the study; correct? 14 A. Yes. 15 Q. It also states that all of the rats in the 16 high-dose study had died at that point; correct? 17 A. Yes. 18 Q. The next lower dose were eating well and gaining 19 weight; correct? 20 A. Yes. 21 Q. And after that came the group that showed 22 hyperirritability, correct -- oh, no, I take that back. I'm 23 sorry. The ones that were gaining weight and eating were 24 exhibiting hyperirritability; correct? 25 A. The rats at the .03 percent in the diet dose are 130 1 the ones I believe that are referred to here as showing the 2 pronounced hyperirritability, yes. 3 Q. In your recitation of the minutes, you state 4 that the group of rats that were suffering from 5 hyperirritability, at least the behavior was observed during 6 the second to the fourth weeks, that had been disappearing; 7 correct? 8 A. Yes. 9 Q. What did that indicate to you as a biochemist? 10 A. I think the interpretation was primarily in the 11 hands of the toxicologists; it didn't indicate anything 12 particular to me, I don't believe. 13 Q. Do you have an explanation whatsoever why this 14 particular group of rats would start exhibiting a pronounced 15 hyperirritability for a period of time? 16 A. No. I would guess that it might be related to 17 their decreased food intake, however. 18 Q. How would that make them hyperirritable? 19 A. When rats are deprived of food, that can happen. 20 Q. Are you saying that these rats were purposely 21 deprived of food? 22 A. No. I'm saying they were not eating as much as 23 the controlled rats were. 24 Q. And when we're talking about this group of rats, 25 we're talking about rats that were on fluoxetine; correct? 131 1 A. That's correct. 2 Q. Is it your recollection that this group of rats 3 initially were not eating? 4 A. I guess there was a decreased amount of eating, 5 not that they were not eating. 6 MR. STOPHER: I believe there was a decreased. 7 A. I believe that there was a decreased amount of 8 eating, not that they were not eating. 9 Q. Do you know if there was a correlation between 10 their eating less and their hyperirritability as far as 11 timewise? 12 A. They were both occurring at the same time, I 13 presume, is that the question? 14 A. Yes. Right. 15 A. I assume they were both occurring at the same 16 time. 17 Q. Is it your understanding or recollection that 18 once they started eating again that the hyperirritability went 19 away? 20 A. I think that's a plausible explanation for the 21 results. Again, I don't have a recollection of this study 20 22 years ago. 23 Q. Could it be that they started eating because the 24 hyperirritability was disappearing? 25 A. I would -- I guess I would not expect that kind 132 1 of relationship but -- no. 2 Q. Do you relate their decrease in eating to the 3 administration of fluoxetine? 4 A. I would imagine that is the cause since in all 5 other respects they would have been like the controlled rats. 6 Q. Do you relate their hyperirritability to the 7 administration of fluoxetine? 8 A. For the same reason I would expect that it was a 9 consequence of the administration of fluoxetine. Again, as I 10 said, probably -- possibly related to their decrease in food 11 intake. 12 MR. SMITH: Your Honor, this might be a point to 13 break. 14 JUDGE POTTER: Okay. Ladies and gentlemen, just 15 put your things in the folder there and leave them in your 16 chair. We're going to take the lunch recess. As I've 17 mentioned to you-all before, do not permit anybody to speak to 18 or communicate with you on any topic connected with this 19 trial, and any attempt to do so should be reported to me. Do 20 not discuss this case among yourselves or form or express 21 opinions about it until it is finally submitted to you. We'll 22 stand in recess till two. 23 (JURORS EXCUSED FOR LUNCH; THE FOLLOWING 24 PROCEEDINGS OCCURRED IN ROOM 148) 25 JUDGE POTTER: I know you told me who Irwin 133 1 Slater is. Tell me who Irwin Slater is. 2 MR. ZETTLER: He's one of the first clinical 3 monitors of the drug. He oversaw testing that was done, wrote 4 protocols, got investigators for Lilly, clinical trials. 5 JUDGE POTTER: And he is a Lilly employee? 6 MS. ZETTLER: Former. 7 MR. MYERS: No. 8 JUDGE POTTER: And this is being put in to go 9 through the mechanics of what Lilly did or is there some -- 10 MS. ZETTLER: No. It's going in to give them a 11 basic background -- very basic background of clinical trial 12 process. It's also going in to demonstrate that the very 13 early trials of the drug were discontinued because they 14 weren't showing efficacy, and very early on there were 15 problems with psychosis and suicidal ideation of the case. 16 MR. MYERS: Let's not argue the case. 17 MS. ZETTLER: I'm trying to give him a 18 background. 19 JUDGE POTTER: Now, tell me, this is his only 20 appearance, he's not going to come later. 21 MR. MYERS: He's not going to come live. 22 JUDGE POTTER: This is just his qualifications. 23 Sustained. All right. So we've got to add to that one. 24 MS. ZETTLER: This is nonresponsive and 25 gratuitous, Judge. 134 1 MR. MYERS: 8 to 11. 2 JUDGE POTTER: Irrelevant means? 3 MS. ZETTLER: That's my argument. 4 JUDGE POTTER: All right. 37. 5 MS. ZETTLER: He's talking about a completely 6 different drug there, Judge. 7 JUDGE POTTER: You want to see if maybe you've 8 got a typo, 10 through 18. 9 MR. MYERS: You're going to read 1 through 20 on 10 Page 37? 11 JUDGE POTTER: And you want to read something 12 out of the next page? 13 MR. MYERS: Yeah. One through 20 on Page 37 14 refers to a request for a larger trial and so does the 15 question on Page 38. 16 MS. ZETTLER: Then he's taking it completely out 17 of context. 18 JUDGE POTTER: (Reading document). Is Ultrine 19 what? 20 MS. ZETTLER: It's another drug. 21 JUDGE POTTER: Another drug? 22 MS. ZETTLER: Right. 23 JUDGE POTTER: Okay. I read it as the same 24 thing. And I assume the point is that they just wanted a 25 bigger trial not because they saw a problem with a drug. 135 1 MR. MYERS: And it's explanatory of the earlier 2 question. 3 MS. ZETTLER: Then let's put this part in, too, 4 then because that makes it sound like fluoxetine. 5 MR. MYERS: Oh, you read a meaning into it I 6 hadn't even thought about. 7 MS. ZETTLER: Yeah. Right. 39. 8 JUDGE POTTER: 39. 9 MR. MYERS: What's the next one? 10 JUDGE POTTER: 39. 11 MS. ZETTLER: If you want to put that part in I 12 don't care about that, that's fine. 13 MR. MYERS: 39 and 40 because that's a 14 continuation. 15 MS. ZETTLER: Right. 16 MR. MYERS: Okay. Thank you. 17 JUDGE POTTER: Those are both by agreement. 18 That gets us to 154. 19 MS. ZETTLER: No. 20 MR. MYERS: 185. 21 JUDGE POTTER: No, 85. 22 MR. MYERS: I'm sorry. 23 MS. ZETTLER: That's fine. 24 MR. MYERS: The 1 to 10? So you're going to 25 read 1 to 10? 136 1 MS. ZETTLER: Yes. 2 JUDGE POTTER: Does that get us -- 3 MS. ZETTLER: Let's go up to 166 and that should 4 get us through the afternoon. 5 JUDGE POTTER: Okay. 154. 6 MR. MYERS: 154, Judge. 7 MS. ZETTLER: Yes. 8 JUDGE POTTER: We need some of this stuff. 9 First noticed that our 24-hour cats often failed to urinate. 10 MS. ZETTLER: Can I see what he wants there? 11 MR. MYERS: 13 to 17. 12 MS. ZETTLER: Make sure everybody realizes how 13 cooperative I'm being, Judge. Make sure everybody realizes 14 that. 15 MR. MYERS: Get us first thing in the morning or 16 the lunch hour it's amazing. What's the next one? 17 JUDGE POTTER: 159. What he wants to do is take 18 this out. 19 MR. MYERS: Lines 3 to 8. 20 MS. ZETTLER: He wants that out. No. That's 21 got to stay in. 22 MR. MYERS: Oh, I put that objection in because 23 it's referencing other compounds. 24 JUDGE POTTER: I don't know Doctor Bennett. 25 MS. ZETTLER: Doctor Bennett is a psychiatrist. 137 1 MR. MYERS: Now deceased or I guess preceded or 2 was a contemporary of Doctor Slater's. 3 MS. ZETTLER: I think the compounds -- if I 4 remember right -- no, because he says trial of this compound 5 and additional compounds it was our judgment that the research 6 would not move forward at a reasonable pace under Doctor 7 Bennett's supervision. That's what I wanted it in for. 8 JUDGE POTTER: Where does he say disappoint? 9 MS. ZETTLER: (Indicating). 10 MR. MYERS: What page are you referencing, 11 Nancy? 12 MS. ZETTLER: 157. 13 JUDGE POTTER: For what it's worth, that can 14 stay in, because if you read back far enough he does say he 15 was discharged. 16 MR. MYERS: Okay. All right. What's the next 17 one? 18 JUDGE POTTER: 165. So what we're talking about 19 is two groups finishing up, filling in a hole. 20 MS. ZETTLER: But what he says is... 21 JUDGE POTTER: Let me read it. 22 MS. ZETTLER: Okay. See, what I think happened 23 here is he says here that they didn't do any test with 24 fluoxetine, but then he starts talking about pergolide 25 studies. So I think he either misunderstood or just jumped. 138 1 MR. MYERS: There's reference to LSD on Page 165 2 and 166 and I'm just filling in for completeness. 3 JUDGE POTTER: You want as much as you can. I 4 mean, it says what it says. If he misunderstood it, it will 5 just have to come out the way it does. 6 (LUNCH RECESS) 7 SHERIFF CECIL: The jury is now entering. All 8 jurors are present. Court is now in session. 9 JUDGE POTTER: Please be seated. Mr. Smith, do 10 you want to continue with the testimony of Doctor Fuller by 11 way of deposition. 12 MR. SMITH: Thank you, Your Honor. 13 JUDGE POTTER: Ladies and gentlemen, I'm going 14 to remind you again, there is a tendency sometimes to treat 15 this as something other than real testimony, okay, and I want 16 to remind you that a deposition, when it's read to you like 17 this is being done, will be treated by you just as if the 18 doctor were here testifying live. 19 Mr. Smith. 20 Q. Beginning on Page 366, Line 7. Any other 21 toxicology studies with animals that you recall where behavior 22 that you relate to fluoxetine was observed? 23 A. Not that I recall. Again, pointing out that I 24 was not involved in the toxicologic studies. 25 Q. You were chairman of the project team during 139 1 that period of time; right? 2 A. Yes. 3 Q. Would the toxicologists doing studies on 4 fluoxetine generally report to you? 5 A. They would report the studies to the project 6 team; they didn't report to me administratively. 7 Q. Would all studies that were being conducted be 8 reported? 9 A. I think so, yes. 10 Q. So if there were other studies out there, you 11 would have at least at one point been made aware of them? 12 A. Yes. 13 Q. Do you recall a dog study where the dogs became 14 aggressive or at least some of the dogs became aggressive? 15 A. No, I don't. 16 MR. SMITH: At this time, Your Honor, we have 17 another exhibit. 18 JUDGE POTTER: Okay. 19 MR. SMITH: This is Plaintiffs' Exhibit 37, 20 which is Fuller Deposition Exhibit 10. 21 SHERIFF CECIL: (Hands copies to Jurors). 22 Q. Have you had a chance to review Exhibit 10? 23 A. I've glanced through it. 24 Q. Do you recognize this exhibit? 25 A. It appears to be a memorandum from Greg Brophy 140 1 dated May 12th, 1981. 2 Q. Do you recall seeing this memorandum before 3 today? 4 A. I'm sure I did. Do I specifically recall it? 5 Nothing rings a bell right now. 6 Q. Do you recall the study that Greg Brophy is 7 talking about in this memo? 8 A. This is a one-year dog study and, yes, I am 9 aware that a one-year dog study was done. 10 Q. Do you recall that, as he says at the bottom of 11 the first page, a total of six dogs from the high-dose group 12 were removed from treatment for periods of 1 to 17 days due to 13 severe occurrences of either aggressive behavior, ataxia or 14 anorexia? 15 A. I didn't recall that prior to reading that 16 sentence, no. 17 Q. Do you recall that in the preceding 90-day dog 18 study, similar CNS toxic signs were seen? 19 A. I did not recall that independently of this 20 memo, no. 21 Q. Do you have an opinion as to what caused six of 22 these dogs in this study to become aggressive, suffer from 23 ataxia or anorexia? 24 A. Well, these are obviously toxic doses and these 25 are simply signs of that toxicity. I have no explanation in 141 1 any sort of specific terms for any of the toxic signs. 2 Q. Were all of these dogs who exhibited these 3 effects of aggressive behavior, ataxia or anorexia, on the 4 same dosage, to your knowledge? 5 A. Were they on the same dose? 6 Q. Right. In the one-year dog study. 7 A. I could only try to ascertain that by careful 8 reading of this document. Would you like me to do that? 9 Q. Sure. 10 A. Well, the sentence says that the six dogs that 11 were removed from treatment because of these occurrences were 12 all in the high-dose group, as a matter of fact, yes. 13 Q. So that would have been the same group, same 14 dosage across the board? 15 A. Yes. 16 Q. It also says in the preceding 90-day dog study 17 at 5, 10 and 20 milligrams per kilogram those dogs exhibited 18 similar toxic signs? 19 A. Yes, it does. 20 Q. Are 5, 10 and 20 milligrams per kilogram in dogs 21 considered to be a high dose? 22 A. Yes, they are. 23 Q. All three of them? 24 A. Yes. 25 Q. Was the issue of agitation in humans using 142 1 fluoxetine raised prior to 1990, to your knowledge, at Eli 2 Lilly? 3 A. I don't have any specific recollection of that. 4 The discussion would most likely have been within the medical 5 division and I might not have participated; but there might 6 have been, in the discussion of the clinical results, that 7 might well have been mentioned along with any other side 8 effects that were observed. 9 Q. How about in the early human trials? Were any 10 adverse reactions such as agitation seen in humans, normal 11 humans given the drug? 12 A. That's what I was referring to. I don't have 13 specific recollection of the listing of side effects and their 14 frequency, but certainly in the discussion of all of the 15 clinical studies that were done, there was careful attention 16 paid to side effects as well as efficacy, and those were 17 tabulated and analyzed and discussed. 18 Q. Do you recall the decision -- a decision being 19 made to allow the use of benzodiazepines for agitations in 20 clinical trials? 21 A. I believe I do remember that. 22 Q. I'm sorry. Your answer was you do recall that? 23 A. I think I do. 24 Q. When was that decision made? 25 A. I couldn't tell you that. 143 1 Q. Do you know what prompted that decision? 2 A. I imagine it was the clinical investigators who 3 were doing the studies felt it was a good idea, because one of 4 the reasons for that would be that, unlike the tricyclic 5 antidepressant drugs, many of which are sedating probably 6 because of their interaction with neurotransmitter receptors 7 as we talked about yesterday. Since fluoxetine does not 8 interact with those receptors and therefore does not have that 9 specific action, then in patients in whom that type of 10 agitation was found, it might take -- it might need a separate 11 drug to treat. 12 Q. And my question is, does fluoxetine exert a 13 stimulating effect? 14 A. In general the answer is no. In animals such an 15 effect is not seen and in humans it typically is not seen. I 16 think there are a few individuals who show an effect which has 17 been described as nervousness, which is not generally 18 described as a stimulant effect, but someone might use that 19 term; I think I would not. 20 Q. Are you saying these are people on fluoxetine? 21 A. Yes. 22 Q. Has that connection between the use of 23 fluoxetine and the nervousness that you talked about been made 24 in those people on fluoxetine? In other words, you said a 25 small percentage of people seemed to exhibit something that 144 1 could be termed as nervousness while on fluoxetine; correct? 2 A. I believe that is one of the side effects that 3 is reported in the package literature. 4 Q. Was the use of benzodiazepine allowed to 5 counteract this effect of fluoxetine in the clinical trials? 6 A. I think in those protocols where it was allowed, 7 it was allowed for the purpose of treating that condition if 8 it occurred, independently of whether it was believed to be 9 caused by fluoxetine or not. 10 Q. So if somebody became nervous on a placebo, they 11 would be given benzodiazepine? 12 A. I believe so. 13 Q. Do you know how many people on placebo became 14 nervous to the point where they had to be administered 15 benzodiazepine? 16 A. No. I have no idea. 17 Q. Do you know how often benzodiazepines were 18 administered to study patients taking fluoxetine? 19 A. No. That is not the type of information I would 20 have. 21 MR. SMITH: We have another exhibit, Your Honor. 22 It's Plaintiffs' Exhibit 38, Fuller Exhibit 11. 23 JUDGE POTTER: I sent my sheriff out. 24 (BENCH DISCUSSION) 25 MR. SMITH: Redacting on these documents were 145 1 done pursuant to the confidentiality order. I would like an 2 instruction to the jury to the same effect that was given in 3 respect to the confidentiality stamp so that the jury won't 4 believe that we're introducing something that's been -- 5 JUDGE POTTER: I'm sure Mr. Myers probably wants 6 the same thing. 7 MR. MYERS: That's fine. 8 (BENCH DISCUSSION CONCLUDED) 9 JUDGE POTTER: Ladies and gentlemen, my sheriff 10 is now going to pass out to you Exhibit No. 38. You will 11 notice on these exhibits in addition to a stamp that says 12 "confidential" or some other writing there are going to be 13 some parts that are blocked out. I'm going to give you the 14 same kind of admonition or instruction I gave you about the 15 confidential stamp or any other stamps on them. You should 16 not draw any inferences or reach any conclusions one way or 17 the other based on the facts that there are certain things 18 marked out. 19 In producing these documents, people marked out 20 certain things, and one reason they were marked confidential 21 was some of these things contain things that are proprietary, 22 business information, and so some of that has been marked out, 23 not to keep it from you -- if it was relevant it would be 24 given to you -- but it's to kind of keep it from the general 25 public or whatever, or at least at the time it was done 146 1 somebody thought it might have some business reason. You'll 2 see some later on where names are marked out, and they're done 3 to keep the privacy of the person that was involved. You'll 4 see some records later on where there are patients or somebody 5 like that that's been involved and the patient's name will be 6 crossed out. There are various reasons why different parts 7 have been crossed out. 8 But what I'm saying is don't draw any inference 9 from it, and obviously what's crossed out is not evidence for 10 you. Do you-all understand what I'm saying? The stamps and 11 the numbers and the cross-outs and all that stuff, don't read 12 anything into it and don't draw any inferences from it because 13 there are probably ten different reasons that certain 14 different areas are crossed out. All right? 15 Okay. Go ahead, Mr. Smith. 16 Q. Before you read that, Doctor, is there a 17 difference in your mind between a person who is agitated and a 18 person who is nervous? 19 A. I would think there is a reason for those two 20 separate words, yes. 21 Q. Okay. What's your definition of somebody who is 22 suffering from agitation? 23 A. I would imagine that would mean a person who is 24 irritated, probably restless. 25 Q. Anything else? 147 1 A. No. 2 Q. How about somebody who was nervous? 3 A. I would imagine the chief difference would be 4 the irritation would not be present. 5 Q. Okay. I'm sorry. Go ahead and look at No. 11. 6 Okay. Have you had a chance to review Exhibit 11? 7 A. Yes. 8 Q. Before we get into that, let me digress a little 9 bit. Do you recognize this exhibit? 10 A. It's a set of project team minutes from July 11 23rd, 1979. 12 Q. And you authored those minutes? 13 A. Yes. 14 Q. On the first page, the first full paragraph 15 under the heading Phase II Clinical Studies and Mental 16 Depression, towards the middle of the paragraph it says, "Some 17 patients have converted from severe depression to agitation 18 within a few days. In one case the agitation was marked and 19 the patient had to be taken off the drug." Do you see that? 20 A. Yes. 21 Q. That doesn't mention nervousness anywhere; 22 right? 23 A. That's right. 24 Q. After that it says, the last paragraph, "In 25 future studies the use of benzodiazepines to control agitation 148 1 will be permitted." Do you see that? 2 A. Yes. 3 Q. Does that refresh your recollection as to why 4 the benzodiazepines were allowed to be used in the clinical 5 trials? 6 A. Yes. 7 Q. Why? 8 A. Well, this use was to control the agitation. 9 I'm not sure that applies necessarily to all the clinical 10 trials, but at least the ones referred to here. 11 Q. So at least as of July of 1979, it was decided 12 by the team that benzodiazepines could be used in the clinical 13 trials for agitation? 14 A. The decision -- that decision would not be made 15 by the project team; that would be made within the medical 16 division. It was reported to the project team. 17 Q. That decision to do that was reported to you as 18 of July 1979? 19 A. Yes. 20 Q. You don't know whether or not the reason for 21 administering benzodiazepines changed at any period of time; 22 correct? 23 A. That is correct. 24 Q. Or whether or not the use of benzodiazepines was 25 actually stopped at any point in time; correct? 149 1 A. I don't know that. That's correct. 2 Q. Phase II clinical studies, were these still the 3 open-label studies that you were talking with Paul about 4 earlier? 5 A. It's impossible to say from this. Phase II 6 clinical studies would have included the open-label studies, 7 but they also included the -- well, the double-blind studies. 8 But as I read further in this document it becomes clear. The 9 third paragraph says, "All studies up to now have been 10 open-label studies and plans are in progress for double-blind 11 controlled studies comparing fluoxetine to placebo, imipramine 12 or amitriptyline." 13 Q. Does this refresh your recollection as to 14 whether or not the use of benzodiazepines to control agitation 15 was going to be permitted in the double-blind controlled 16 studies as well as any other open-label studies that were 17 going to be done? 18 A. I would infer from what is written here that 19 that would be the case. 20 Q. Did anybody at Lilly have any concern that the 21 use of benzodiazepines may be -- might be masking a side 22 effect profile of this drug? 23 A. I could not answer that question. I don't know 24 what all the people at Lilly might have thought. 25 Q. How about you? Were you concerned that it might 150 1 have masked the side effect profile of the drug? 2 A. I don't remember discussing the issue in the 3 project team. It's the sort of issue that would have been 4 discussed within the medical division. 5 Q. Do you have an opinion now, whether or not 6 giving benzodiazepines to people who became agitated on 7 fluoxetine would in effect mask a side effect profile of 8 fluoxetine? 9 A. Well, my knowledge is fairly general as a 10 noncommission, but as a pharmacologist who has some knowledge 11 of psychopharmacology, I think the likelihood of there being a 12 masking is unlikely because the use of benzodiazepines would 13 certainly be recorded, so if there was an increased use of 14 benzodiazepines in this group there would be a record of that. 15 Q. If you could go back to Exhibit 11, again, the 16 first paragraph on the first page, it talks about clinical 17 studies in mental depression proceeding under modified 18 protocols use higher doses of fluoxetine. Do you see that? 19 A. Yes. 20 Q. Do you know why it was decided to use higher 21 doses of fluoxetine at that time? 22 A. No. I do not have specific knowledge of the 23 reason for that. Doses up to 60 milligrams and even higher 24 had previously been given in Phase I studies, for example. 25 But, apparently, from what I read here, these specific 151 1 protocols for these studies had not included higher doses, and 2 it's apparent that someone, possibly the investigators, felt 3 that that would be important to do. 4 Q. Does this imply to you that the people who 5 converted from severe depression to agitation within a few 6 days converted because of the use of fluoxetine? 7 A. That's certainly one possibility. As I 8 discussed earlier, in an open-label study of this sort without 9 any information on the frequency with which this occurs in 10 treated patients -- patients treated with fluoxetine versus 11 patients who would be treated with placebo, it's difficult to 12 make a judgment about cause and effect. 13 Q. What to your knowledge was done on the part of 14 Eli Lilly to investigate the possible relationship between the 15 fluoxetine use and the occurrence of violent, aggressive 16 behavior in human beings? 17 A. Are you asking this question in the context of 18 the earlier one, what was done? 19 Q. No. I'm asking you this question in the context 20 of the question. To your knowledge, what did Eli Lilly do to 21 investigate the claim that fluoxetine use could produce 22 violent, aggressive behavior in human beings? 23 A. So the question is, after the claim was made 24 what was done to investigate that? 25 Q. Right. 152 1 A. That was what I was asking for clarification on. 2 One of the major things that was done was a very careful 3 reanalysis of the entire data base from the controlled 4 clinical studies to investigate whether in fact there was any 5 evidence to support such claims. And while I was not involved 6 in that and I'm not intimately familiar with it, I am aware 7 that the results of that, I believe, were published with John 8 Heiligenstein as first author, and they suggest, I believe, as 9 many people might have predicted from the rather extensive 10 literature that surrounds the possible role of serotonin in 11 aggressive behavior, based more on animal studies than human 12 studies, that indeed there was a reduced incidence rather than 13 an increased incidence in the fluoxetine-treated patients. 14 Q. What else was done besides this careful 15 reanalysis of the data base? 16 A. At the moment I don't recall the other things 17 that would have been done, but I would not have been involved 18 in those other things personally. 19 Q. To your knowledge, were any double-blind 20 controlled studies set up to specifically study this 21 phenomenon? 22 A. Any further studies beyond those which have been 23 done? 24 Q. Yeah. 25 A. Not that I recall. 153 1 Q. To your knowledge, were the studies that were 2 reanalyzed, were any of those studies set up specifically to 3 -- to specifically study that phenomenon? 4 A. They were not, so far as I know. 5 Q. Are you aware of any studies that Lilly did on 6 schizoaffective disorders and the use of fluoxetine treating 7 it? 8 A. If such studies were done I'm sure I heard about 9 them, and I don't have specific recollection of that. 10 Q. What makes you say that this was -- that the 11 reanalysis was a careful reanalysis of the data base? 12 A. Because I am sure those people who were doing it 13 were very concerned with a careful study of the data to find 14 out if there was any basis for the statements that some people 15 were making. 16 Q. Any other reason besides that reason? 17 A. I think that's the main reason. 18 Q. Do you know exactly which studies they 19 reanalyzed or which data they reanalyzed? 20 A. I believe it was virtually all of the controlled 21 double-blind studies that were available at that time. 22 Q. Both the United States and outside the United 23 States? 24 A. I have no involvement and I could not answer 25 that specific question, and I think it would have -- well, 154 1 period. 2 Q. If not all the controlled studies were 3 reanalyzed would that have an impact on the validity of the 4 reanalysis, in your mind? 5 A. I don't know the answer to that question. 6 Q. You don't have an opinion either way as to 7 whether or not it would have an impact on the validity of the 8 analysis whether or not all of the studies were actually 9 reanalyzed? 10 A. So far as I know, all the studies that had 11 useful information were analyzed, and if there were studies 12 that were not included, there would have been some reason, 13 which I don't know. 14 Q. Who decided whether or not a particular study 15 had useful information? 16 A. I would have no way of knowing that. 17 Q. Did you have any input whatsoever in the 18 manuscript that Doctor Heiligenstein wrote? 19 A. No, I did not, to the best of my recollection. 20 Q. How about suicidality related to the use of 21 fluoxetine? What did Lilly do to investigate that issue once 22 it arose? 23 A. I believe the same thing, a reanalysis of all 24 the available data and, I believe, a careful monitoring of all 25 future reports of any sort. 155 1 Q. When you say future reports of any sort, what do 2 you mean? 3 A. Any information that would have come in from any 4 source pertaining to that topic. 5 Q. In your opinion, are the clinical investigators 6 used by Lilly to conduct the double-blind controlled studies 7 competent individuals, generally? 8 A. The intent is certainly to select competent 9 individuals. I would have not much basis for making those 10 judgments myself because I have little participation in the 11 selection of the clinical investigators. 12 Q. Have you ever seen any clinical report forms 13 from any particular double-blind controlled studies? 14 A. I believe I have seen them. 15 Q. Have you reviewed them? 16 A. No. 17 Q. Have you done a study of the results that were 18 -- an independent study on your own of any of the results of a 19 particular clinical trial? 20 A. No. 21 Q. Earlier you stated that if the benzodiazepines 22 were in fact given to treat agitation suffered by people who 23 were on fluoxetine that as long as -- and if I'm getting this 24 wrong, let me know -- but as long as the adverse event itself 25 was recorded it wouldn't necessarily mask a side-effect 156 1 profile of fluoxetine to administer the benzodiazepines; is 2 that correct? 3 A. Yes. I think what I said was that not only the 4 event would be recorded but also the use of benzodiazepines 5 would be recorded. 6 Q. If the use of benzodiazepines was recorded but 7 the event was not recorded, would that impact the validity of 8 that particular clinical trial result, in your opinion? 9 A. Well, you may be asking about details that I 10 would have no way of knowing, but the recording of 11 benzodiazepine use, I assume, would itself signify an event. 12 So I'm not sure how you could have one without the other. 13 Q. Did you yourself write any papers on fluoxetine 14 and violent, aggressive behavior? 15 A. Specifically on the subject of fluoxetine and 16 violent, aggressive behavior, no. 17 Q. How about fluoxetine and aggressive behavior? 18 A. I have written a lot of papers on fluoxetine or 19 on the subject of serotonin pharmacology, and in the context 20 of some of those papers I have talked about various aspects of 21 serotonin, physiological roles of serotonin in the brain, and 22 certainly in some of those papers there would be mention of 23 aggressive behavior. So that the words fluoxetine and 24 aggression, for example, might, I would imagine, have both 25 appeared in some of the papers I have written. 157 1 Q. Prior to the issue being raised in the media, 2 was Lilly studying whether or not there was a relationship 3 between the use of fluoxetine and violent, aggressive 4 behavior? 5 A. I don't believe so. 6 Q. How about the use of fluoxetine and suicidal 7 ideation or suicidal behavior? 8 A. Well, I think that would be inherent in the 9 study of depression, since suicidal ideation and behavior are 10 components of -- common symptoms of depression. 11 Q. I mean as a specific issue, not as a portion of 12 the depression study. 13 A. So far as I know, not as any study that wasn't a 14 depression study. 15 Q. Were you involved in the registration of 16 fluoxetine in any country other than the United States? 17 A. What do you mean by involved? 18 Q. Did you have any input on information that was 19 given to any other governmental agency outside the USA, or did 20 you perform studies in support of any application in any other 21 country by Lilly for marketing of fluoxetine? 22 A. Well, certainly the same preclinical data that I 23 generated that were included reported to the United States 24 Food and Drug Administration were also reported to other 25 regulatory agencies, and in some cases I probably wrote 158 1 summaries of the pharmacologic data for other agencies. As 2 far as dealing directly with any agencies in other countries, 3 I did not. 4 Q. Are you aware that patients that posed a serious 5 suicidal risk were excluded from the outpatient clinical 6 trials? 7 A. In Germany, you are referring to? 8 Q. No. In the United States. 9 A. I probably was aware of that. 10 Q. Do you know why they were excluded? 11 A. Well, I would remind you that I was not involved 12 in the planning or monitoring of the clinical trials, so I do 13 not have any intimate knowledge of the protocols or the 14 reasons for their design, but I would imagine that if that 15 condition as you described occurred, it was because it was the 16 best judgment of the clinical investigators that the interest 17 of the patient would be best served by not including them in 18 the study. 19 Q. Do you recall how many inpatient studies of 20 suicidal patients were conducted by Lilly using fluoxetine 21 prior to January 1st, 1990? 22 A. No. I would have no reason to know that. 23 Q. Have you done studies specifically comparing the 24 effects of fluoxetine and the effects of amphetamines on lab 25 animals? 159 1 A. I have done research on amphetamine for probably 2 at least 25 of the 31 years I have been at Eli Lilly and 3 Company, and I have done research on fluoxetine for -- what 4 would it be -- 22 years, so I have done a fair number of 5 pharmacological experiments on these two drugs, yes. 6 Q. Why is it your opinion that the two drugs are 7 not similar, if you can just give me a general -- are not 8 similar. 9 A. Fluoxetine is a selective inhibitor of serotonin 10 uptake and it does not have any other relevant pharmacologic 11 actions, as far as we are aware. Amphetamine does not have 12 that pharmacologic action; instead, its principal 13 pharmacologic effects are as a releaser of catecholamines, 14 particularly dopamine and norepinephrine. It has a set of 15 pharmacologic actions that result from the release of 16 catecholamines which are, for the most part, totally different 17 from the pharmacologic actions of serotonin uptake inhibitors 18 such as fluoxetine. 19 Q. How about the behavioral effects of the drugs; 20 are there similarities? 21 A. There's virtually no similarity. 22 Q. Do lab animals on amphetamines demonstrate a 23 lowered food intake? 24 A. I wouldn't personally include that in a list of 25 behavioral effects. The one thing that drugs which release 160 1 dopamine do that is common -- that is in common with the drugs 2 which block serotonin uptake or release serotonin is reduce 3 appetite, and that's because food intake is regulated not only 4 by serotonergic neurons but also by catecholamine neurons to 5 the brain. So it's possible to reduce food intake by 6 affecting either of those neuropathways, and the 7 characteristics of drugs which act through those two distinct 8 pathways are quite different. The reduction of food intake 9 that is elicited by amphetamine is readily distinguishable 10 from the reduction in food intake that is elicited by 11 fluoxetine, in that, for example, fluoxetine selectively 12 reduces carbohydrate intake, as other drugs acting through the 13 serotonin mechanism do, and which amphetamine does not do. 14 Fluoxetine suppresses the insulin-induced hyperphagia, 15 overeating in rats, which amphetamine and other 16 catecholamine-acting drugs do not do. And fluoxetine reduces 17 stress-induced eating in rats, which amphetamines and other 18 drugs acting through a catechol mechanism do not do. So the 19 effects of fluoxetine and amphetamine on food intake are 20 readily distinguishable from one another. 21 Q. The fact of the matter is you're looking at the 22 two rats, both of them are eating less, correct, for whatever 23 reason? 24 A. If that's all you're looking at, you would see a 25 decrease in both cases. 161 1 Q. How about agitation? Have you seen agitation in 2 both rats on fluoxetine and rats on amphetamines? 3 A. As I have testified earlier, we do not see any 4 observable behavioral changes in rats treated with fluoxetine; 5 in rats treated with amphetamine, observable behavioral 6 changes are very apparent. There is pronounced hyperactivity, 7 and this can be observed or it can be quantitated in various 8 kinds of cage devices that measure -- that allow one to 9 measure hyperactivity. And the studies that have been done 10 show clearly that fluoxetine does not cause that 11 amphetamine-type of hyperactivity. 12 Q. How about sleep disturbance? Do you see sleep 13 disturbance in both animals? 14 A. No. So far as I know, fluoxetine causes no 15 changes in sleep that I would characterize as sleep 16 disturbance. 17 Q. Decreased REM sleep is not a sleep disturbance? 18 A. I was not done with my answer, but I can 19 incorporate an answer to the second question in my 20 continuation. 21 With amphetamine, while I do not remember 22 studies specifically on sleep, knowing what amphetamine- 23 treated rats look like, I would feel sure that if you studied 24 them during a period in which they were normally sleeping, 25 they would not be sleeping with amphetamine. And these 162 1 studies that you are referring to, I imagine, on REM sleep 2 that were done by Doctor Slater and his colleagues and also 3 done by Doctor Pastel and colleagues at the University of 4 Pittsburgh, I believe all showed that there was no decrease in 5 total sleep time in rats that were treated with fluoxetine -- 6 or, in cats, I believe. And the reduction, the significant 7 reduction in REM sleep that was observed is a change only in 8 one quantitatively rather minor component of sleep, and I 9 don't think most people would refer to that as a sleep 10 disturbance. 11 Q. You think REM sleep is a minor portion of sleep? 12 A. Quantitatively it is, yes. 13 Q. Are you talking about -- are you talking about 14 in animals as well as humans or just in animals? 15 A. The data I'm referring to are in animals, rats 16 and cats, yes. 17 Q. Do you feel that REM sleep is quantitatively a 18 minor portion of the sleep cycle in humans? 19 A. I think it probably is. 20 Q. Are you aware that REM sleep deprivation in 21 human beings has produced psychosis in some studies? 22 A. No, I'm not specifically aware of that, although 23 I may have seen publications on that subject. 24 MR. SMITH: Your Honor, we have Plaintiffs' 25 Exhibit 39 that we'd offer at this time. 163 1 SHERIFF CECIL: (Hands exhibit to Jurors). 2 Q. Okay. Have you had a chance to review Exhibit 3 13? 4 A. I've seen it and glanced through it. 5 Q. Do you recognize it? 6 A. It appears to be a collection of E-mail messages 7 that relate to the subject that we discussed earlier. 8 Q. And that subject meaning whether or not 9 fluoxetine acts as a stimulant or has amphetamine-type 10 properties? 11 A. That's correct. 12 Q. Who is Hans Weber. 13 A. Hans Weber I believe was and maybe still is the 14 Lilly medical representative in Germany. 15 Q. Who asked you for this information on the 16 chemicals structures -- comparative chemical structures of 17 fluoxetine and amphetamines? 18 A. I would have to review this to see if the answer 19 is apparent here because I don't remember it. Well, this 20 seems to indicate that on February 6th, 1991, Doctor Leigh 21 Thompson sent a message to me. 22 Q. Are you referring to the fourth page of the 23 exhibit? 24 A. Yes, I am. 25 Q. Okay. Doctor Thompson is asking you about the 164 1 abuse potential, is he not? 2 A. Yes. 3 Q. And I mean abuse potential of fluoxetine; 4 correct? 5 A. That is correct, I believe. 6 Q. And that apparently is in response to an inquiry 7 by the BGA? 8 A. It is apparently in response to the message 9 which is immediately below his message saying from Hans Weber. 10 Q. Okay. And in that message he states that 11 fluoxetine was discussed extensively at a meeting apparently 12 between the BGA and AMK? 13 A. Yes. 14 Q. And towards the bottom of the page there are 15 three bullet-type differentiations; do you see those? 16 A. Yes. 17 Q. The last one says, "Also the question was raised 18 whether fluoxetine could be an amphetamine-like drug which may 19 explain stimulating and anorexic effects." Do you see that? 20 A. Yes, I do. 21 Q. And it goes on to say that it turned out that 22 not enough was known about the pharmacology in this respect; 23 correct? 24 A. Yes. I see that. 25 Q. The one on the first page of the exhibit that 165 1 says, "I find it surprising that anyone would consider the 2 chemical structure of fluoxetine and amphetamine to be 3 similar," and your explanation that follows after that. 4 A. I recall that I have, on occasion, actually 5 drawn out the chemical structures of many of these drugs 6 mentioned on this page because, to me, it was so absurd that 7 anyone would suggest a chemical similarity between fluoxetine 8 and amphetamine. And I have suggested to people that they 9 might show that page of structures and ask people to pick out 10 which compounds they viewed to be structurally similar, and if 11 anyone who didn't know what those drugs were would ever have 12 pointed to the fluoxetine molecule as being similar to the 13 amphetamine molecule, I would have been greatly surprised. 14 Q. Let's try my question again. Did you provide 15 Doctor Thompson or anybody else information, such as results 16 studies, medical literature, scientific literature, drawings 17 of the different chemical structures in response or in support 18 of your response that is here -- set out here in Exhibit 13? 19 A. I think what I just described to you was indeed 20 information that would pertain to this, and I think what I 21 said was I remember preparing that; what I do not remember is 22 whether or not I supplied that at this time to either Doctor 23 Thompson or anyone else. 24 Q. Okay. Besides the drawing and the explanation 25 of the drawings, did you give them any scientific literature, 166 1 any papers? 2 A. Well, I referred in this message to the fact 3 that in November 1985, Martin Hynes, David Wong and myself 4 prepared a report on fluoxetine and its preclinical 5 pharmacology in which there was references given and reprints 6 supplied that document several of the points that I made in 7 this message. 8 Q. Anything else besides that report? 9 A. I remind you that I have told you I don't 10 remember whether I sent anything in relation to this 11 particular E-mail message, but that on different occasions I 12 have provided such information to anyone who hs asked for it. 13 Q. How about directly in response to questions 14 raised by the BGA? 15 A. This is in response to a question raised by the 16 BGA. This particular response is just that. 17 Q. Right. 18 A. If you are asking were there others, I do not 19 know; there may have been. 20 Q. Who is Professor Mueller-Oerlinghausen? Look at 21 the third-from-the-last page. 22 A. He's a psychiatrist in Germany. 23 Q. Does he work for the BGA? 24 A. I don't know. Doesn't work full time for the 25 BGA, I don't believe. 167 1 Q. The last paragraph on PZ2576 1702, which is the 2 page we were just looking at states Professor 3 Mueller-Oerlinghausen can take this point back to the next 4 meeting if armed with specific information. Do you recall 5 whether or not he was working with or consulting with the BGA 6 at that time? 7 A. I don't even know if I was aware of it at the 8 time, and if I was I don't recall it now. He apparently had 9 some involvement. 10 Q. And the next page it says, "Detailed information 11 would be most appreciated. Also, M-O -- which I take to mean 12 Mueller-Oerlinghausen -- knows Ray Fuller and a direct 13 telephone contact might help." Do you see that? 14 A. Yes, I do. 15 Q. Did you call Doctor Mueller-Oerlinghausen? 16 A. Not to the best of my recollection, no. 17 Q. Were you asked to, besides this E-mail? 18 A. I doubt it. 19 Q. Why do you doubt it? Why do you doubt that you 20 were asked? 21 A. I don't remember being asked; let me say it that 22 way. 23 Q. Also in the last -- I guess it's in the last 24 page of the exhibit, first middle of the page it says, "Ray, 25 David, Lou, Rich -- what package of information can we gather 168 1 from -- gather for Professor Mueller-Oerlinghausen?" 2 A. Yes. 3 Q. It says, "He is very objective and played a key 4 role with the BGA through the AMK." What is the AMK? 5 A. I don't know. 6 Q. Who is Bob Thompson? 7 A. Bob Thompson is a physician in our medical 8 division. 9 Q. Is he still there? 10 A. Yes, he is. 11 Q. Is serotonin metabolized any way other than 12 being retaken back up into the neuron? 13 A. That step is not actually referred to as 14 metabolism. The metabolism of fluoxetine is the -- is its 15 degradation by the enzyme monoamine oxydase and that is by far 16 the principal route of serotonin metabolism. 17 Q. Where does the degradation by the MAO take 18 place? 19 A. It takes place -- the enzyme monoamine oxydase 20 is located on the outer membrane of mitochondria and virtually 21 every cell in the body has mitochondria-containing monoamine 22 oxydase and therefore is capable of metabolizing serotonin. 23 The serotonin in the brain is metabolized within the brain 24 since it does not cross the blood brain barrier. 25 Q. Okay. If the serotonin molecule is not taken 169 1 back up into the serotonin neuron, does it remain active? 2 A. By "active" I assume you mean active on a 3 receptor to transmit nerve impulses. 4 Q. Or capable of being active on a receptor to 5 transport impulses? 6 A. Yes. As long as it remains as an intact 7 serotonin molecule it would be capable of interacting with a 8 receptor if it comes in contact with one. 9 Q. I can't remember if it was you or Doctor Wong 10 who testified to this, but can the -- what is meant by the 11 serotonin at the site -- transport site not being able to get 12 in because of the fluoxetine diffusing; do you recall saying 13 something like that? 14 A. Yes. Fluoxetine, any molecule will diffuse 15 through biological fluids, so if it is -- if a molecule such 16 as fluoxetine -- such as serotonin is released at some 17 particular site, if it were not actively transported back up, 18 it would in time diffuse out away from that site. 19 Q. How much time after it's released into the site? 20 A. Well, there's -- I don't know the answer. There 21 would be physical laws which would influence the rate at which 22 it diffuses, and there probably would be some rate in 23 microliters per second or something of that sort, but I don't 24 know that because that's not considered very relevant to 25 serotonin, to an understanding of serotonin physiology. 170 1 Q. When you say it's not considered relevant, 2 considered relevant by whom? 3 A. By those people who are investigating serotonin 4 physiology. 5 Q. People outside of Lilly as well as at Lilly? 6 A. Yes. 7 Q. When you say extracellular, do you mean outside 8 the, for instance, serotonin neuron? 9 A. Yes, I do. 10 Q. So it's that serotonin that has been released by 11 the neuron? 12 A. Yes. 13 Q. Is it fair to say that the reason that you 14 believe that the concentration of serotonin after fluoxetine 15 administration remains the same in the synaptic cleft is 16 because it remains the same in the brain tissue that's 17 studied? 18 A. That's inaccurate. Serotonin concentration in 19 the synaptic cleft does not remain the same. Serotonin 20 concentration in the synaptic cleft increases as a result of 21 blocking the uptake site with fluoxetine. 22 Q. How do you know that? 23 A. By measurement of the amount of extracellular 24 serotonin and by the various functional changes that occur as 25 a consequence of blocking the uptake carrier. 171 1 Q. The measurement of extracellular serotonin in 2 the synaptic cleft itself? 3 A. As I explained when we discussed this earlier, I 4 may not have explained it in complete detail so I'll do that 5 now. There are different ways by which the extracellular 6 concentration of serotonin has been shown to be increased 7 after fluoxetine administration, and these have evolved as 8 technology has advanced for being able to make these 9 measurements. The first measurement was -- involved a 10 fleurometric technique by Mark Geyer and colleagues at the 11 University of California in San Diego, who used a technique 12 which they called abbreviated fading, F-A-D-I-N-G, and what 13 they showed is that drugs like monoamine oxydase inhibitors 14 increased the amount of serotonin inside of neurons, whereas 15 fluoxetine increased the amount of serotonin outside the 16 neuron in the synaptic cleft. The next technique to be 17 applied was a technique called -- 18 Q. Let me stop you there real quick. That 19 technique specifically showed that there was an increase of 20 serotonin at the synaptic cleft, in the synaptic cleft? 21 A. In the extracellular fluid. 22 Q. And the extracellular fluid is limited 23 specifically to the synaptic cleft? 24 A. No. The extracellular fluid is everywhere 25 outside the cell. 172 1 Q. So they measured the increase in serotonin in 2 the fluid generally outside the cell? 3 A. Yes. 4 Q. There is no way of knowing if the fluid was 5 localized or that the serotonin was localized in any way at 6 the synaptic cleft? 7 A. It certainly would not all be within the 8 synaptic cleft, but that would be the initial site of its 9 release, so you would expect that that would be among the 10 places where it would be increased. 11 Q. That's an assumption made because of the 12 concentration found in the fluid itself? 13 A. It may be. Since I'm not an expert in that 14 technique, I couldn't comment on the ability with which those 15 investigators were able to distinguish between a synaptic 16 cleft concentration versus another extracellular 17 concentration. I don't know. 18 Q. Okay. I'm sorry. Go ahead. 19 A. The second technique was called in vivo 20 voltametry, and it was pioneered by Ralph Adams and his 21 colleagues at the University of Kansas. And he, I believe, 22 while he was on sabbatical in the UK, collaborated in a study 23 in which the investigators showed that a voltametric signal, 24 which they had several pieces of evidence to suggest was 25 serotonin, was increased in response to fluoxetine. 173 1 Q. With that second method that you've just 2 described, is there any way to differentiate between 3 concentrations of serotonin in the synaptic cleft as opposed 4 to the concentration with other -- another extracellular 5 fluid? 6 A. No. As I think I said yesterday, the size of a 7 synaptic cleft is smaller than the size of a probe that one 8 would use to measure the extracellular concentration. So you 9 could not insert a probe directly into a synaptic gap. 10 Q. Okay. 11 A. The third line of evidence was a result of 12 studies using push/pull cannula technique, which I believe I 13 did describe yesterday, and this is the most quantitative of 14 the techniques that I mentioned so far, and it involves the 15 withdrawal of a small amount of extracellular fluid from some 16 particular site in the brain. And investigators at Indiana 17 University Medical Center showed that fluoxetine 18 administration caused a several-fold increase in extracellular 19 concentrations of serotonin using that technique. 20 And the fourth and final technique, which is the 21 newest and I think far and away most elegant certainly 22 completed quantitative technique is the brain microdialysis 23 method. And that has been shown by several groups of 24 investigators, including ourselves, Ken Perry and my 25 laboratory, fluoxetine has been shown to cause a several-fold 174 1 increase in extracellular serotonin in several regions of the 2 rat brain that has been studied. 3 Q. And that last technique again, can you in any 4 way differentiate between the concentration of serotonin at 5 the synaptic cleft and that in the fluid generally? 6 A. No. I think what has been measured is 7 extracellular fluid and, as I mentioned yesterday, there are 8 serotonin neurons, in fact, that don't even make synaptic 9 contact with other neurons. 10 Q. Okay. And the third method you said would be 11 true as far as measuring how much is in the -- what the 12 concentration in the actual cleft is would be true of the 13 third method, the push/pull? 14 A. That's correct. 15 Q. What's a synaptosome? 16 A. A synaptosome is a small particle which should 17 be thought of essentially as a pinched-off nerve ending. When 18 one homogenizes brain tissue the endings of nerves actually 19 pinch off into little sacs which are called synaptosomes and 20 they retain many of their functions, including the ability to 21 take up monoamines. So a synaptosome from a serotonin nerve 22 terminal would retain the ability to take up serotonin. A 23 synaptosome from a dopamine nerve terminal would retain the 24 ability to take up dopamine, and so preparations of the 25 synaptosomes are used in the study of the transport of each of 175 1 these transmitters. 2 Q. Just -- can a synaptosome still create or 3 release serotonin? 4 A. Yes. They can release serotonin. 5 Q. Is that because -- yesterday I think you said 6 that a serotonin neuron can release serotonin because of an 7 electrical pulse that it is receiving from another neuron or 8 from an electrical pulse that's created spontaneously? 9 A. Yes. 10 Q. So because it can create these spontaneously 11 they can still release serotonin, the synaptosomes? 12 A. Well, the synaptosomes wouldn't be releasing 13 serotonin because it's only a small part of the serotonin 14 nerve terminal. It wouldn't generate action potentials and 15 actually release serotonin by itself, but you can do things to 16 the synaptosomes which will trigger the release, such as add 17 drugs like fenfluramine, which release serotonin or add high 18 concentrations of potassium which would release that 19 serotonin. So it is possible to study release from the 20 synaptosomes just the same as one can study uptake by the 21 synaptosomes. 22 Q. How much does a neuron fire spontaneously? 23 A. Well, I don't know that I can explain the 24 mechanics of that very well. I think what I was referring to 25 yesterday is that a neuron may undergo a very regular pattern 176 1 of firing that appears to be not in response to a signal from 2 some other neuron, but when other neurons then alter their 3 input to that, this may be speeded up or slowed down. 4 MR. SMITH: Your Honor, at this time, Your 5 Honor, we would offer Plaintiffs' Exhibit 40, which would be 6 Fuller Exhibit 14. 7 SHERIFF CECIL: (Hands document to Jurors). 8 Q. Have you had a chance to look at Exhibit 14? 9 A. Yes, I have. 10 Q. Have you seen this before? 11 A. I'm sure I have. It's a report from the 12 fluoxetine -- the minutes of a fluoxetine project team meeting 13 in July 1978. 14 Q. The first paragraph of Exhibit 14 talks about 15 three trials in depression having started and another one 16 about to start; correct? 17 A. Yes. 18 Q. These are still open-label studies, as far as 19 you know? 20 A. Well, that is not specifically stated in these 21 minutes, but from what is said a year later it's apparent that 22 they were. 23 Q. The first paragraph of the second page at the 24 top states, "None of the eight patients who completed the 25 four-week treatment showed distinct drug-induced improvement." 177 1 Correct? 2 A. Yes. 3 Q. Is that drug-induced meaning fluoxetine-induced? 4 A. Yes. 5 Q. And another patient had improved but the 6 improvement started during the placebo period before drug 7 treatment was started; correct? 8 A. Yes. 9 Q. The next paragraph starts out talking about a 10 fairly large number of reports of adverse reactions. Do you 11 see that? 12 A. Yes. 13 Q. Is this your opinion or is this information 14 related that was discussed during the meeting? 15 A. It's information that was discussed during the 16 meeting. 17 Q. Who would have given you that information at 18 that time? 19 A. Whoever was the clinical monitor at that time, 20 and among the addressees, the person that that would be would 21 be Doctor Shulman. 22 Q. Shulman? 23 A. Yes. 24 Q. Okay. The second paragraph on the second page 25 of the exhibit goes on to talk about different types of 178 1 adverse reactions reported; correct? 2 A. Yes. 3 Q. At the bottom of that paragraph it says, 4 "Another depressed patient developed psychosis, manifested by 5 paranoid delusions while taking fluoxetine." Do you see that? 6 A. Yes. 7 Q. Also, it goes on to say akathisia and 8 restlessness were reported in some patients. Do you see that? 9 A. Yes. 10 Q. To your knowledge, was any determination made as 11 to whether or not these adverse reactions were as a result of 12 taking fluoxetine? 13 A. I don't think I know what kind of determination 14 you would be thinking about. 15 Q. Any determination of whether or not it was -- 16 there was a causal relationship between the use of fluoxetine 17 and, say, for instance, this patient developing psychosis and 18 manifesting it by paranoid delusions? 19 A. I don't know how one would determine that in an 20 individual patient, short of repeating the treatment at some 21 later time and, so far, I know that was not done. 22 Q. Why not? 23 A. I could not answer that, having not been 24 involved in the design of those clinical studies or their 25 execution. It may have been -- I can only speculate. 179 1 Q. Do you understand the term rechallenge, 2 rechallenging a patient? 3 A. I think I do, but if you have something specific 4 in mind, I'd appreciate it. 5 Q. My understanding of what it means to rechallenge 6 a patient is, say, for instance, using this person who 7 developed psychosis. Say that this person was not suffering 8 from psychosis, they were placed on fluoxetine, they developed 9 psychosis and then were taken off of fluoxetine and then the 10 psychosis disappeared. Okay? Rechallenging would then be to 11 place them back on the fluoxetine to see if the psychosis 12 reappeared. Is that a fair description of rechallenging? 13 A. That would be a reasonable description, yes. 14 Q. Is that what you mean when you say short of -- 15 A. Yes. That is what I meant by one approach to 16 ascertain if an effect was due to a drug. 17 Q. As a biologist do you consider that a 18 scientifically valid method of testing, whether or not there 19 is a relationship between a particular event and a use of a 20 particular drug? 21 A. As a scientifically valid method, I suppose the 22 short answer would be yes. 23 Q. Why were cerebrospinal fluids samples taken from 24 patients who participated in Phase II projects as reflected on 25 the last paragraph of the second page of Exhibit 14? 180 1 A. The purpose, as I recall, was to ascertain if 2 the doses of fluoxetine being used were sufficient to inhibit 3 serotonin uptake, the expectation being that if they were, 4 there would be a decrease in cerebrospinal fluid levels of 5 5-HIAA. 6 Q. What were the results of the analysis of the 7 cerebrospinal fluid, at least as reflected in this exhibit? 8 A. Well, according to this report, one patient 9 showed a decrease in 5-HIAA from 39 to 31 nanograms per 10 milliliter and no nanograms per milliliter. 11 Q. Would that -- are you done? I'm sorry. 12 A. One patient showed a reduction in the 13 accumulation of 5-HIAA-induced by probenecid, which is a drug 14 that decreases or inhibits the transport of the 5-HIAA out of 15 the brain. 16 Q. Okay. As far as those people on fluoxetine then 17 whose 5-HIAA levels decreased, would you expect them under 18 your theory of serotonin neurotransmission to exhibit signs of 19 decreased depression? 20 A. There are two separate and distinct facts which 21 need to be laid out, I think. One is that in some depressed 22 patients who are not being treated with any drug, there could 23 be a reduced concentration of 5-HIAA in the cerebrospinal 24 fluid, and the interpretation that is made by from that 25 finding is that there was a decreased amount of serotonin 181 1 being formed and released and that might possibly have been 2 related to the disease. 3 A second fact is that when one gives a 4 serotonin-uptake inhibiting drug there is a decrease in 5 serotonin turnover, one manifestation of which is a decrease 6 in 5-HIAA concentration as measured in animals in brain 7 tissue. But, of course, one cannot measure that in humans in 8 brain tissues; therefore, the measurement would be in the 9 cerebrospinal fluid. So the change in 5-HIAA after a drug 10 such as fluoxetine is given, if there is a decrease in 5-HIAA 11 that would indicate that serotonin uptake has been inhibited 12 and then, as a consequence of that inhibition, one might 13 expect that there would be an alleviation of the present 14 symptoms. 15 Q. And do these levels to which these two patients 16 5-HIAA decrease, would that indicate to you that there was 17 inhibition of uptake resulting from administration of 18 fluoxetine occurring? 19 A. Yes. That would be the interpretation. 20 Q. Do you know if either one of these patients 21 showed signs of drug-induced improvement? 22 A. No. I do not know that. 23 Q. Why would their levels, their metabolic levels 24 and they would not show increased improvement? 25 A. I think... 182 1 Q. Assuming that the reduction in the 5-HIAA meant 2 that serotonin was not being retaken into the neuron? 3 A. It was certainly known by the investigator 4 treating the patients whether those patients improved or not. 5 It wasn't recorded in the minutes, and it may not have been 6 known to the project team at that time because the information 7 might not have been a study having not been completed. The 8 information might not have been transmitted by the 9 investigators so that the question of whether those patients 10 improved or not clinically is simply one that I don't know the 11 answer to. 12 Q. Can you tell from this exhibit whether or not 13 the patients from which cerebrospinal fluid samples were taken 14 discussed at the bottom of the page were members of the 15 eight-patients group who completed the four-week treatment? 16 A. No, you cannot tell. 17 Q. And then the next page, the last full paragraph 18 of the page talks about a school of thought under which a 19 subgroup of depressed patients were thought to be identified 20 by measuring 5-HIAA concentrations in the cerebrospinal fluid. 21 Do you see that? 22 A. Yes. 23 Q. Do you agree with that? 24 A. Yes. I agree that was a school of thought. 25 Q. Do you agree that that was a possibility or is a 183 1 possibility identifying the subgroup of depressed patients 2 deficient in serotonergic function? 3 A. That appears to be a possibility, yes. 4 Q. Has Lilly, to your knowledge, ever done such 5 studies to determine whether or not it's possible to identify 6 a subgroup of depressed patients who are deficient in 7 serotonergic function? 8 A. I think there may have been Lilly-sponsored 9 studies in which 5-HI levels were measured in the 10 cerebrospinal fluid, studies other than this one. 11 Q. Do you know who conducted those studies? 12 A. I know there are -- no, I don't. 13 Q. Do you know if the results of those studies were 14 published by Lilly or anybody else who has conducted such 15 studies? 16 A. No. I don't remember. 17 Q. Doctor Fuller, do you know all the causes for 18 suicidal ideation? 19 A. Do I know all the causes? 20 Q. Yeah. 21 A. No, I don't. 22 Q. Are you competent to render an opinion on the 23 causes of suicidal ideation? 24 A. I don't think so. 25 Q. Do you know all the causes for suicide in 184 1 humans? 2 A. No, I do not. 3 Q. Are you competent to render an opinion about the 4 causes of suicide in humans? 5 A. Certainly not any sort of informed medical 6 opinion, no. 7 Q. To your knowledge, did Lilly publish any medical 8 bulletins, journals, studies, findings, between the years of 9 1987 and 1981 that would suggest that there was a causal link 10 between the use of Prozac and suicidal ideation or suicide in 11 humans? 12 MR. STOPHER: '87 and '81? It's '91? 13 Q. '91. 14 A. No, not to my knowledge. 15 Q. Did you personally? 16 A. No, I did not personally. 17 Q. During the period of '87 to '91, did Lilly 18 publish any documents, articles, medical treatises that would 19 suggest that a physician should administer a sedative to a 20 patient who is ingesting Prozac? 21 A. That is not something I'm likely to know. To my 22 knowledge, the answer would be no. 23 Q. You did not personally? 24 A. I did not personally. 25 MR. SMITH: That concludes the deposition of 185 1 Doctor Ray W. Fuller, M.D., Your Honor. 2 JUDGE POTTER: Ladies and gentlemen, we'll go 3 ahead and take the afternoon recess. As I've mentioned to 4 you-all before, do not permit anybody to talk to you about 5 this case. Do not discuss it among yourselves and do not form 6 or express opinions about it. Stand in recess for 15 minutes. 7 (RECESS) 8 SHERIFF CECIL: All jurors are present. 9 JUDGE POTTER: Please be seated. Mr. Smith, do 10 you want to call your next witness. 11 MR. SMITH: Yes, Your Honor. At this time we 12 request permission to read portions of the deposition of Irwin 13 Slater, M.D. 14 JUDGE POTTER: Ladies and gentlemen, I'm going 15 to mention to you again that a deposition is sworn testimony. 16 It's taken outside the courtroom prior to trial. The witness 17 is placed under oath. Each side has an opportunity to be 18 present and examine and cross-examine that witness just the 19 way they do at trial. In this particular case, there was a 20 transcript made of that testimony and that transcript will now 21 be read to you and you will give this -- these questions and 22 answers the same weight you would as if the witness were here 23 testifying live. Mr. Smith. 24 (MR. SMITH & MR. FOLEY READ THE FOLLOWING 25 TESTIMONY FROM THE DEPOSITION OF DR. IRWIN 186 1 SLATER) 2 MR. SMITH: The deposition of Irwin Slater taken 3 at the offices of Paulich and O'Hara, 2150 Goodlette, Naples, 4 Florida on January 28th and 29th, 1994; said deposition taken 5 pursuant to notice in accordance with the Rules of Civil 6 Procedure. Direct examination by Mr. Smith: 7 Q. Would you state your name? 8 A. Irwin Slater. 9 Q. I believe you told us off the record, Doctor 10 Slater, that you were 76 years old? 11 A. Yes. 12 Q. May I have your residence address, please? 13 A. 2101 Tarpon Road, Naples, Florida 33962. 14 T-A-R-P-O-N, like the fish. 15 Q. When were you last employed? 16 A. Formally full time my last employment was with 17 Eli Lilly and Company and I retired at the end of 1979. I did 18 have a part-time responsibility as editor of Clinical and 19 Experimental Hypertension for which I was paid a pittance, and 20 I resigned from that position about two years ago. 21 Q. Is Clinical and Experimental Hypertension a 22 scientific publication? 23 A. Yes. 24 Q. You are a medical doctor; is that correct? 25 A. Yes. 187 1 Q. Would you tell us, Doctor, Slater, what your 2 educational background is beginning with high school, where 3 you graduated from high school and when and bring us through? 4 A. I'm proud to do that. I was graduated from 5 Erasmus Hall High School in Brooklyn, New York, which high 6 school was found in 1787. I attended the University of 7 Virginia in Charlottesville where I obtained a Bachelor's 8 Degree in 1937; New York University College of Medicine, an MD 9 in 1941. My education continued in the sense as I interned at 10 Beth Israel Hospital in New York, 1941 to 1942. I was in the 11 United States Navy from 1942 through 1946. In 1946 I returned 12 as a resident in medicine at Beth Israel Hospital and a 13 part-time instructor in pharmacology at New York University 14 College of Medicine. After completing the residency, I 15 practiced medicine in New York and became an instructor in the 16 pharmacology at NYU. From 1949 to 1954, I was instructor and 17 assistant professor of pharmacology at the University of 18 Rochester. At various times I was a visiting professor at 19 Indiana University and the University of Illinois in Chicago. 20 Q. Now, was it during the period of time that you 21 were completing your residency that you began instructing in 22 pharmacology at New York College of Medicine -- New York 23 University College of Medicine? 24 A. The first year of the residency was a year to be 25 devoted to basic research and I was assigned to the 188 1 pharmacology department at the New York University where I had 2 worked even as a medical student. And then the second year 3 was as a supervisor of the other residents, I was chief 4 resident of medicine so the clinical experience was the 5 seconds year. The first year was mostly in research, but I 6 did have some rudimentary contact with patients during the 7 first year. 8 Q. Was that first year of study, was that devoted 9 to pharmacology or internal medicine? 10 A. Yes, pharmacology. 11 Q. And then when did you begin your private 12 practice? 13 A. In July of 1949 -- '48. 14 Q. In Rochester? 15 A. No. New York City. 16 Q. But then shortly thereafter moved to Rochester? 17 A. I had the opportunity to do full-time research 18 in pharmacology and I decided that I enjoyed that more than 19 clinical practice, so I went to the University of Rochester 20 where I was a member of the pharmacology department. 21 Q. And were you a professor of pharmacology from 22 1949 to '51? 23 A. No. I was instructor, then assistant professor 24 until I was invited to come to Eli Lilly and Company. 25 Q. When was that? 189 1 A. 1954. 2 Q. Are you board certified, Doctor Slater, in any 3 particular specialty? 4 A. No. 5 Q. When you were in private practice did you ever 6 hold yourself out as a specialist in pharmacology? 7 A. No. 8 Q. The short period of time that you were in 9 private practice, what did your practice consist of? 10 A. It was just mostly a few patients each day who 11 were referred to me by various people. 12 Q. Would that have been an internal medicine 13 practice? 14 A. It was more a general practice. 15 Q. Then when did you join Eli Lilly and Company, 16 you said 1954, but do you have a date? 17 A. Yes. September. 18 Q. When did you first develop an interest in 19 pharmacology? 20 A. In my second year of medical school. 21 Q. In medical school did you have any courses in 22 neuropsychopharmacology? 23 A. No, I don't think. 24 Q. Was there even such a thing then? 25 A. That's what I was going to say, no. 190 1 Q. Have you ever had any courses in 2 neuropsychopharmacology? 3 A. I have mostly given them rather than taken them. 4 Q. When did you first become conversant in 5 neuropsychopharmacology? 6 A. When I went to Rochester. 7 Q. What type of experience did you have at the 8 University of Rochester in connection with 9 neuropsychopharmacology? 10 A. Well, it was -- my initial research was in 11 centrally acting muscle relaxants, and then after the second 12 year my responsibilities continued in that general field but 13 we did research in other sections of pharmacology that were 14 more basic in nature. 15 Q. Did you do any work on central nervous system 16 pharmacology? 17 A. We studied anticonvulsant drugs. 18 Q. Was that about the extent of 19 neuropsychopharmacological drugs was antiseizure drugs? 20 A. And muscle relaxants. 21 Q. Do muscle relaxants work on the nervous system 22 or on the muscle system? 23 A. The nervous system. 24 Q. By the time you completed your work at the 25 University of Rochester, was the scientific knowledge such at 191 1 that time that there was any belief or any documentation that 2 brain chemistry could affect mood? 3 A. I think at that point the field was emerging. 4 Q. In what respect? 5 A. Doctor Brodie had published papers on the role 6 of serotonin as a possible neurotransmitter. This is Bernard 7 Brodie at the National Institute of Health. 8 Q. Were you employed with Eli Lilly and Company 9 from 1954 until December 31st 1979; correct? 10 A. Yes. 11 Q. What was your first job in connection with your 12 employment at Eli Lilly and Company? 13 A. I was a senior pharmacologist. 14 Q. Where were you working for Lilly Research Labs 15 or Eli Lilly and Company? 16 A. It's the same thing. The component that I was 17 in was Lilly Research Laboratories and I was in the division 18 of pharmacology. 19 Q. Was your work there research work or what 20 exactly were you doing as a senior pharmacologist when you 21 began at Lilly? 22 A. I was assigned to do research in the central 23 nervous system. 24 Q. And specifically what were you researching in 25 connection with the central nervous system? 192 1 A. Well, the first paper I wrote was on a research 2 analog called Recanecine, or something like that, in general 3 to find drugs that would be useful in treating mental illness 4 of various types. 5 Q. Were you doing research to investigate various 6 compounds that were being investigated by Lilly as potential 7 CNS active drugs? 8 A. Yes. 9 Q. Can you give me the names of any compound that 10 later became marketed by Lilly? I'm not interested in 11 potential drugs that were tested and never got on the market, 12 but what were some of the first drugs that you researched that 13 were eventually marketed by Lilly? 14 A. Phenaglycodol, I think, that's called Ultren. 15 Q. When was it first marketed by Lilly? 16 A. Probably 1955 or '56. 17 Q. What was that drug used for? 18 A. It was a neurosedative. 19 Q. For sleep, to reduce agitation? 20 A. To reduce anxiety. 21 Q. Is Ultren still on the market? 22 A. No. 23 Q. When was -- when did Lilly cease marketing 24 Ultren? 25 A. About 1960, I guess. 193 1 Q. Why did they discontinue that product? 2 A. It must have been later than that, more likely 3 about 1969 or '64. The original clinical trials demonstrated 4 that when carefully compared with other neurosedatives that 5 Lilly -- that Ultren was at least as good as or better than 6 these compounds. These were based on a limited number of 7 patients. The FDA wanted a much larger study and the company 8 didn't think that they could afford the size trial that the 9 FDA wanted, so rather than undertake the trial, they agreed to 10 withdraw the compound from the market. 11 Q. But was it actually marketed? 12 A. It was on the market and also it was marketed in 13 a combination with Darvon called Darvitran. 14 Q. Darvon was a Lilly medication that had already 15 been -- was already on the market; is that correct? 16 A. Yes, but -- yes. 17 Q. But the Ultren was a separate and independent 18 medication? 19 A. Yes. 20 Q. That was given -- it was an antianxiety agent? 21 A. Uh-huh. 22 Q. Whereas Darvon is primarily a pain medication, 23 is it not? 24 A. Yes. 25 Q. In '63 or '64, the FDA requested a larger 194 1 clinical trial? 2 A. Uh-huh. 3 Q. Involving more subjects than had been previously 4 tested? 5 A. Yes. 6 Q. Was there a particular problem with the drug 7 that it caused the FDA to ask? 8 A. No. 9 Q. What other while you -- how long were you a 10 senior pharmacologist, by the way? 11 MS. ZETTLER: I've lost the place here. 12 MR. SMITH: Page 39, Line 16. 13 MS. ZETTLER: You want to read it again? 14 MR. SMITH: I'll read the question to you again. 15 Q. What other while you -- how long were you a 16 senior pharmacologist, by the way? 17 A. About a year. 18 Q. So would that be 1954 to 1955? 19 A. Yes. 20 Q. Did you work on any other compound that was 21 marketed as a central nervous system agent? 22 A. I worked on Mephihexital, which is Brovital, 23 which is a short acting anesthetic. 24 Q. Is it still on the market? 25 A. Yes. 195 1 Q. Which is primarily used as a short-term acting 2 anesthetic? 3 A. Induction of anesthesia. 4 Q. Any other CNS medications that you worked on 5 while you were a senior pharmacologist? 6 A. Well, the time frame is a little bit loose. In 7 1955, I became head of the department of neuropharmacology. 8 It was just a change in title and gave me a responsibility for 9 supervising the work of other people, but my own laboratory 10 work continued, and I can't say with a great deal of detail 11 what I did between the change in responsibility. 12 Q. How long were you the head of the department of 13 neuropsychopharmacology? 14 A. Until I became director, let's see, until there 15 was a big reorganization and I think I became a research 16 adviser. I'm not exactly sure, but I think that happened 17 about 1958 or '59. Then there was another reorganization a 18 couple of years later and I became director of pharmacological 19 research. 20 Q. When did you become director of pharmacological 21 research at Lilly, approximately? 22 A. Maybe 1965, maybe a little earlier. 23 Q. And how long were you the director of 24 pharmacological research? 25 A. Until about 1972. 196 1 Q. Up until -- from 1955 until 1972, you were in 2 CNS, central nervous system medications? 3 A. Yes. 4 Q. Doctor Slater, in connection with your work on 5 all these CNS active drugs -- and when I say CNS active drugs 6 can we understand that I'm talking central nervous system 7 active drugs? 8 A. Yes. 9 Q. And that would be drugs that act on the brain 10 and nerves; is that right? 11 A. Brain and spinal cord. 12 Q. What was the first clinical trial that you 13 participated in at Eli Lilly and Company? 14 A. Fluoxetine. 15 Q. When did you first engage in clinical trials in 16 connection with fluoxetine or Prozac? 17 A. 1978. 18 Q. Up until fluoxetine, you had never been a 19 medical monitor or been an individual who had been in charge 20 of administering a clinical trial in connection with any 21 compound? 22 A. That's true. I had, what shall I say, reviewed 23 data with people who had tested the various central nervous 24 system drugs that we had developed and had gone over the data 25 with them so I knew how clinical trials were supervised, but I 197 1 never had personal responsibility for communicating directly 2 with the expert investigators who were actually testing the 3 drug. 4 Q. When you say expert investigators, you're 5 talking about investigators out in the field? 6 A. Yes. 7 Q. At various sites during the actual clinical 8 trials? 9 A. Yes. 10 Q. I understand that. But my questions right now 11 deal with the first time you had ever been responsible for the 12 administration of clinical trials was in 1978, with fluoxetine 13 hydrochloride; is that correct? 14 A. That's correct. 15 Q. Prior to that your work had been limited to 16 pharmacology on site at Lilly? 17 A. Yes. 18 Q. Now, had you done any work in connection with 19 fluoxetine hydrochloride, Prozac, before you began doing the 20 clinical trial administration in 1978? 21 A. Yes. 22 Q. Tell us what your first work was in connection 23 with fluoxetine hydrochloride. 24 A. My own personal work involved two experiments -- 25 three experiments. The first experiment was done in 198 1 anesthetized cats to determine whether the compounds had any 2 effects on the cardiovascular system. 3 Q. Let me stop you just a second. When was that 4 experiment done? 5 A. Probably 1972, I would say, '73. 6 Q. How long did that experiment last? 7 A. A matter of weeks. 8 Q. How many cats do you recall were used in that 9 study or experiment? 10 A. Probably a dozen or so. 11 Q. Tell me how you -- 12 A. This is just off the top of my head. It could 13 be more or less. 14 Q. I understand. I would assume when you're giving 15 the specific information in connection with something done 20 16 years ago, you don't remember the number of cats you put to 17 sleep? 18 A. That's possible. 19 Q. Tell me about -- we'll call it the cat 20 experiment. 21 A. I don't remember anything except that they 22 didn't show anything that concerned us. 23 Q. The purpose of that experiment, would it be 24 correct, Doctor Slater, to say that the purpose of that 25 experiment was to examine whether or not fluoxetine 199 1 hydrochloride had any effect on the heart of cats? 2 A. Yes. 3 Q. And your recollection is that your experiment 4 with 12 cats didn't demonstrate any effect that fluoxetine 5 hydrochloride had on those cat hearts? 6 A. Right. 7 Q. What was the next experiment? 8 A. We had a colony of cats with electrodes 9 implanted in various sites in the brain and we were studying 10 the effects of drugs on sleep patterns in cats. 11 Q. Let's call that first experiment with the cats 12 and cardiovascular research the heart experiment. 13 A. Yes. 14 Q. Let's call this one the -- 15 A. Sleep experiment. 16 Q. Sleep experiment. 17 A. Uh-huh. 18 Q. How many cats were used in that study? 19 A. I guess our colony consisted of a dozen or so 20 cats and probably all of them received the compound several 21 times. 22 Q. How long did it last? 23 A. Probably several months. There's a paper there 24 that we could check the exact number of cats, if you're 25 interested. 200 1 Q. Only mildly. What were the results of that 2 experiment? 3 A. The result of the experiment showed that 4 fluoxetine was remarkable in causing a suppression of REM 5 sleep. 6 Q. Remarkable in causing a suppression of REM 7 sleep. Now, let's put that in layperson's terms, Doctor 8 Slater. Does that mean that these cats slept better or worse? 9 A. Different. 10 Q. Different. How different? 11 A. They had no REM sleep. 12 Q. What is REM sleep? 13 A. REM sleep is a sleep associated with fast 14 activity, fast activity in the brain waves from surface 15 electrodes and spiking from the genicular body. 16 Q. I thought we were going to talk about layperson 17 stuff. REM means rapid eye movement, does it not? 18 A. Yes. 19 Q. And is the quality of sleep involving REM sleep 20 different than other types of sleep? 21 A. REM sleep is the sleep that occurs usually with 22 dreaming and it occurs in humans at intervals about an hour 23 and a half and cats in about intervals of 30 minutes and then 24 goes on for a period of time and then reverts back to 25 slow-wave sleep. 201 1 Q. What is the significance that fluoxetine caused 2 a remarkable increase in suppression of REM sleep? 3 A. I think in my mind it was the fact that Doctor 4 Vogel at the University of Chicago had postulated that it was 5 characteristic of antidepressant drugs to suppress REM sleep. 6 Q. From that were you postulating that fluoxetine 7 hydrochloride had antidepressant properties because it also 8 suppressed REM sleep? 9 A. That was the inference. 10 Q. So in that experiment you demonstrated that 11 fluoxetine hydrochloride actually caused a difference in the 12 quality of sleep of cats? 13 A. Yes, sir. 14 Q. You demonstrated that the ingestion of 15 fluoxetine hydrochloride in those cats resulted in a physical 16 change in physiology or the body functions of those cats; is 17 that right? 18 A. Yes. 19 Q. Is REM sleep something that's considered 20 necessary in humans or desirable in humans? 21 A. In the original paper by Doctor Dement, he 22 proposed that deprivation of REM sleep might have deleterious 23 effects, but he later retracted that view and I don't think 24 that it's the current view that it is essential and, as I 25 said, Doctor Vogel postulated that the absence of REM sleep 202 1 seemed to have therapeutic -- seemed to be associated with 2 therapeutic effects of -- there's a reference to Doctor 3 Vogel's paper either in this paper or one of the others. 4 Q. In any event, this experiment demonstrated 5 specifically that fluoxetine hydrochloride, Prozac, caused 6 physiological changes in these cats? 7 A. Yes. 8 Q. It caused their brain to act differently than it 9 had done prior to their being given this Prozac, this 10 fluoxetine hydrochloride? 11 A. Yes. One wouldn't expect a drug to have 12 therapeutic effects on the brain unless it had some effect 13 there. 14 Q. Well, we know from reviewing the clinical trial 15 data and the summaries of FDA approval and everything, that 16 fluoxetine hydrochloride was found by the Food and Drug 17 Administration to be no more efficacious -- efficacious than 18 any other antidepressant currently marketed and that's the 19 reason for my questions is that it does -- even though it's no 20 more efficacious than any other antidepressant, fluoxetine 21 hydrochloride in your findings certainly did indicate some 22 specific changes in brain chemistry in animals in this study; 23 is that correct? 24 A. Studies indicated that all the other 25 antidepressants will the same effects. 203 1 Q. Were there other experiments that were done 2 during that time by other researchers at Lilly? 3 A. Yes. 4 Q. Few or many? 5 A. Many. 6 Q. Can you give me the names of the individuals who 7 were principally involved in that research? 8 A. Doctor Fuller and Doctor Wong. 9 Q. Probably certainly wouldn't understand it. Was 10 it your -- was it with your encouragement that Doctor Fuller 11 and Doctor Wong and Doctor Molloy developed and synthesized 12 fluoxetine hydrochloride? 13 A. No. Not entirely. Doctor Molloy had been 14 enacting with the various people in pharmacology and doing a 15 great deal of reading and felt there was a possibility of 16 developing an important antidepressant drug. He and Doctor 17 Rathbun set up a screen to find such a drug and I suggested to 18 Doctor Wong that he should do biochemical studies on the 19 compound that were coming out of the screen that Doctor Molloy 20 were submitting to Doctor Rathbun. 21 Q. Who was Doctor Rathbun? 22 A. Doctor Rathbun was a pharmacologist in charge of 23 examining the preliminary effects of drugs on mice. 24 Q. When was that that you made the suggestion that 25 these individuals coordinate their work? 204 1 A. I reviewed my diaries to find out when that was 2 and I'm not exactly sure. It was very early in the study 3 itself. It's not in the diaries. 4 Q. Is this diary in chronological order? 5 A. Yes, I think so. 6 Q. The first entry that I see is in November of 7 1970. 8 A. Yes. 9 MR. SMITH: Your Honor, at this time, we would 10 offer the diary, which is marked Plaintiffs' Exhibit 41, which 11 was Slater Exhibit 2. 12 JUDGE POTTER: This is it? 13 MR. SMITH: Yes, sir. 14 SHERIFF CECIL: (Passing exhibit out to jurors). 15 Q. Wong, Fuller and Molloy, they were the ones who 16 were actually involved in this discovery? 17 A. Yes. 18 Q. You were the director of the group that they 19 were in; is that right? 20 A. I wasn't the director in the sense that I told 21 them what to do, I was the senior member, the oldest man 22 around, and one who had been around longest and had perhaps 23 the broadest experience, but I was not directing what they do. 24 This is one of the reasons why I was considered such a poor 25 administrator because I didn't try to tell people what to do. 205 1 I felt that the creativity came from science and not from 2 marketing people. My motto was marketing can tell you with a 3 great deal of accuracy what researchers should have been doing 4 ten years ago. 5 Q. I take it your area was in research and not 6 marketing? 7 A. Yes. 8 Q. I you were never involved in the marketing of 9 any products of Eli Lilly and Company? 10 A. No. 11 Q. Is that right? 12 A. True. 13 Q. Did you call any psychiatrist or 14 neuropsychopharmacologist in any discussions in connection 15 with fluoxetine during this period of time? 16 A. I don't think so. 17 Q. Did you call any experts in who were familiar 18 with and actually study the mental illness of depression? 19 A. At this time? 20 Q. Yes. 21 A. No. 22 Q. Did you call in any experts or any individuals 23 who were specifically knowledgeable concerning issues 24 presented by suicide and suicidality during this period of 25 time? 206 1 A. No. 2 Q. Did you consult with any individuals who were 3 expert or knowledgeable in connection with violent/aggressive 4 behavior at this time? 5 A. No. 6 Q. Were you involved in the first clinical studies 7 in connection with fluoxetine hydrochloride? 8 A. No. 9 Q. Who was? 10 A. Doctor Shulman. 11 Q. He was the one responsible for administration of 12 the clinical trials just before you? 13 A. Yes. 14 Q. Was there anybody that was responsible for the 15 administration of the clinical trials before Doctor Shulman 16 that you were aware of? 17 A. Yes, of course, Doctor Lemberger. 18 Q. Was Doctor Lemberger involved in Phase 1 or 19 Phase 2? 20 A. Phase 1. 21 Q. Was Doctor Shulman in Phase 1 or Phase 2? 22 A. Phase 2. 23 Q. What is your understanding of the differences in 24 Phase 1 and Phase 2 clinical trials? 25 A. Phase 1 is to establish in general terms the 207 1 safety and the bioviability and life of a compound in a 2 patient. 3 MR. SMITH: Read the rest of that answer at Line 4 21 -- 22. 5 MR. FOLEY: I see it. "It determines how a 6 compound is handled by normal people from which one can infer 7 duration of action and so on." 8 Q. Well, in the Phase 1 clinical trials under 9 Doctor Lemberger, would it it be accurate to state that all of 10 the subjects, all the individuals who had participated in the 11 Phase 1 clinical trials were individuals that would be 12 considered normal, healthy individuals? 13 A. I can't swear to it but I would assume so. 14 Q. In other words, those Phase 1 clinical trials 15 should exclude individuals who were suffering from a diagnosis 16 of depression? 17 A. Presumably. 18 Q. Did you do any work at all in connection with 19 the Phase 1 clinical trials? 20 A. No. 21 Q. Do you recall when the Phase 2 clinical trials 22 began? 23 A. No. But I would guess in retrospect that it 24 would be about 1976. 25 Q. And in the Phase 2 clinical trials, would it be 208 1 accurate to state that that would be the first time that human 2 beings who were suffering from depression were first given 3 fluoxetine hydrochloride, later known as Prozac? 4 A. Yes. I think so. 5 Q. Why did you become the medical monitor or 6 clinical trial administrator of fluoxetine hydrochloride in 7 1978? 8 A. Doctor Shulman had done very few studies and had 9 determined that he was unable to demonstrate any clinical 10 efficacy. We in pharmacology and in the preclinical research 11 components were very happen -- 12 MR. STOPHER: Very unhappy. 13 A. -- were very unhappy because we felt that these 14 studies had been inadequate and we made our unhappiness known. 15 When there was a reorganization in which I was totally removed 16 from administrative responsibility, the director of medical 17 research indicated that since I was going to retire in another 18 year, would I be willing during the last year of my employment 19 to make some attempt to determine whether the company should 20 or should not have further interest in fluoxetine. Is that 21 clear? 22 Q. Yes. Who was this individual? 23 A. The name is Doctor Ian, I-A-N, Shedden, 24 S-H-E-D-D-E-N. 25 Q. And what was Doctor Shedden's title at that 209 1 time? 2 A. He was a vice-president in charge of medical 3 affairs. This may not be accurately his title but defines his 4 responsibilities as I remember them. 5 Q. Is Doctor Shedden still with Eli Lilly and 6 Company? 7 A. No. 8 Q. Is he still alive? 9 A. I don't know. 10 Q. Where was he when you last saw him? 11 A. He had gone back to England. 12 Q. When did he leave Lilly, as far as you know? 13 A. About 1983, I would guess, maybe '84. 14 Q. Did he go back to England with Lilly or did he 15 cease his employment with Lilly and move back to England? 16 A. He ceased his employment. 17 Q. Was he an older or younger gentleman than you? 18 A. I think a little bit younger than I. It got to 19 the stage where almost everybody was younger than I. 20 Q. Well, as I understand it from what you said, 21 Doctor Shulman's work in the opinions of you who were involved 22 in the preclinical studies was not adequate, it had 23 demonstrated that fluoxetine was not efficacious in treating 24 individuals who were depressed; is that right? 25 A. Yes. 210 1 Q. And you and others in your group believed that 2 his work was either erroneous or had not been done with enough 3 insight or vigor to demonstrate the efficacy of this product 4 as an antidepressant? 5 A. Yes. 6 Q. Who was joining you at this time in raising 7 these concerns with respect to the early Phase 2 clinical 8 trials done by Doctor Shulman? 9 A. Doctor Fuller, Doctor Wong, Doctor Molloy and so 10 on, the people who had worked so hard in the preclinical 11 phases. 12 Q. How did you and Fuller, Wong, and Molloy voice 13 your concerns in this connection? Did you write memos, did 14 you write rebuttals to the clinical trials that were done 15 under Doctor Shulman? How did you make this known? 16 A. I won't swear to the thing, but I think we did a 17 great deal of bitching around the company. 18 Q. I was trying to avoid saying that even though 19 that's what I was hinting at. How did you make your bitching 20 known to your boss? 21 A. I really don't remember, but we apparently got 22 the point across. 23 Q. And your campaign -- actually you were in a 24 campaign to further the clinical trials to demonstrate the 25 efficacy of fluoxetine hydrochloride? 211 1 A. To test the hypothesis that interfering with 2 serotonin reuptake would be a useful way to treat some 3 depressed patients. 4 Q. As I understand it, the early clinical trials 5 done by Doctor Shulman failed to demonstrate any efficacy in 6 treating depressed patients; is that right? 7 A. Yes. 8 Q. But you felt that the medication that is 9 influencing serotonin would indeed -- if brought further along 10 would demonstrate some capacity or propensity -- 11 A. To help people. 12 Q. -- to help depressed individuals? 13 A. Yes. 14 Q. So was their thought of discontinuing clinical 15 trials on fluoxetine hydrochloride completely at this time? 16 A. They had been completely discontinued. 17 Q. When was that that they completely discontinued 18 the early Phase 2 clinical trials? 19 A. 1977. 20 Q. Who would have been responsible for making that 21 decision? 22 A. Doctor Shulman. 23 Q. What was Doctor Shulman's position at that time? 24 A. I guess he was -- had the title -- he was the 25 senior physician assigned to do research on drugs expected to 212 1 have benefit in patients with various mental illnesses. He 2 was formerly trained as a psychiatrist. 3 Q. Do you know who Doctor Shulman would have been 4 responsible to? 5 A. Doctor Marsden. 6 Q. Would Doctor Shulman have had to secure Doctor 7 Marsden's approval to discontinue the fluoxetine trials as he 8 did? 9 A. Presumably. 10 Q. Did you talk to Doctor Shedden before he came to 11 you and made this proposal to you? 12 A. No, I don't think so. 13 Q. Why don't you think it over. 14 A. No. I was sort of surprised when he invited me 15 to take it over. 16 Q. Give me the details of how that came up, your 17 conversations with him. 18 A. My recollection was that I was invited to come 19 to his office and I wondered what he wanted to see me about. 20 Q. Why was that, because he was such a bigwig? 21 A. No, because it was not something that I had been 22 invited to do before. 23 Q. All right. 24 A. And I should perhaps mention that several years 25 before when Doctor Shedden first came to Lilly, I had told him 213 1 about the activity of fluoxetine in animals and I was pleased 2 that he as a clinician clearly understood the implications of 3 the findings that we had and seemed to be interested. And so 4 when I went to his office, I knew that this was a man who 5 understood what problems were and he said to me, "Irv, would 6 you be willing during the months that you will still be with 7 Lilly to undertake supervising a clinical trial to determine 8 whether fluoxetine might or might not be an active drug. My 9 mission was clearly limited to making the decision, should we 10 do extensive trials with this drug or should we accept the 11 decision to discontinue it. 12 Q. All right. So the decision had been made to 13 discontinue? 14 A. Yes. 15 Q. By Doctor Shulman? 16 A. Yes. 17 Q. The psychiatrist who had been the early Phase 2 18 trials in connection with depressed individuals; is that 19 right? 20 A. Yes. 21 Q. Did he say why your retirement would have any 22 effect on you being the man with the responsibility for 23 directing these Phase 2 clinical trials on depressed 24 individuals? 25 A. He said it was to be a limited effort. 214 1 Q. In what respect was it to be a limited effort? 2 A. We were only to have funds sufficient to secure 3 three investigators and collect enough clinical data to enable 4 a final decision on whether to continue or discontinue the 5 drug trials. 6 Q. What happened to Doctor Shulman? 7 A. He left Lilly and took a job in a San Antonio 8 firm. 9 Q. Did you have any kind of strong or harsh 10 disagreement with Doctor Shulman concerning this yourself? 11 A. No. 12 Q. Did you ever confront him and say, "Doctor 13 Shulman, I think you're wrong in this decision to kill the 14 clinical trials on Prozac"? 15 A. I can't recall ever having talked to him about 16 it. 17 Q. But you did talk to other individuals at Lilly 18 in connection with your opinion? 19 A. Because he left the company rather soon after 20 his exposure to fluoxetine, I think he stayed with Lilly only 21 for a year or two. 22 Q. Was he fired? 23 A. No. He had a -- he just moved on. 24 Q. Okay. So you were going to get three 25 investigators? 215 1 A. Uh-huh. 2 Q. And you were going to collect only enough data 3 to determine whether or not the study should continue; is that 4 right? 5 A. I don't like the emphasis on the only, but to 6 collect enough data. 7 Q. You thought -- the reason I said only was not to 8 try to put words in your mouth but to properly characterize it 9 because I thought you were going to have limited funds and 10 since this decision was being reviewed and since you were only 11 going to have a short time there yourself, that this was 12 something that you were going to have some specific parameters 13 with respect to the time you could spend and the money that 14 you could spend on this project? 15 A. Yes. 16 Q. Is that accurate? 17 A. Yes. 18 Q. And so you were going to collect in the short 19 time and money that you had a somewhat limited amount of data 20 in connection with the clinical trials that you were going to 21 do; correct? 22 A. Yes. 23 Q. How did you select these three individuals as 24 investigators? 25 A. They were recommended to me by members of the 216 1 group who had been reading the literature. 2 Q. Who were the members of the group that 3 recommended these three investigators? 4 A. Doctor Stark and Doctor Fuller. 5 Q. What was Doctor Stark's function at the time you 6 took over the Prozac, fluoxetine hydrochloride clinical 7 studies? 8 A. I think at that time Doctor Stark had been 9 assigned to the medical division as an individual who would 10 supervisor clinical trials of various types. 11 Q. Well, do you know whether or not Doctor Stark 12 had supervised any fluoxetine clinical trials prior to your 13 taking over? 14 A. Yes, I do know. 15 Q. Had he? 16 A. No. 17 Q. Doctor Stark is not a medical doctor, is he? 18 A. He is not. 19 Q. Doctor Fuller is not a medical doctor, either, 20 is he? 21 A. No. 22 Q. But you took those individuals' recommendations 23 as individuals who could recommend particular investigators 24 for this resumption of clinical trials -- 25 A. Yes. 217 1 Q. -- on fluoxetine; is that correct? 2 A. Yes. 3 Q. Was Doctor Louis Fabre one of the individuals 4 that was asked to do one of the studies? 5 A. Yes. 6 Q. And Doctor Fabre is in Houston, Texas? 7 A. Yes, he was then. I don't know if he is now. 8 Q. He's still there, in between trips to Mexico. 9 He still practices in Houston, Texas. What were the protocol 10 numbers that these three investigators did in these studies? 11 A. What do you mean by protocol numbers? 12 Q. Well, the new investigators did studies 13 according to protocols, did they not? 14 A. Yes, I guess. 15 Q. What is your understanding of what a protocol 16 is? 17 A. It's a plan of how you're going to do an 18 experiment. 19 Q. It's sort of a blueprint for the study, isn't 20 it? 21 A. Yes. 22 Q. Did you do any research yourself in connection 23 with how to conduct a clinical trial on humans before you 24 began administration of the fluoxetine clinical trial? 25 A. I'm not sure I understand what you mean. 218 1 Q. Did you do any research -- I understand you 2 talked to Doctor Stark and Doctor Fuller about individuals to 3 hire to do these clinical trials? 4 A. Oh, I did considerable reading in the field to 5 see how such studies were being done, but I don't think I 6 could cite page and reference to what I read 20 years ago. 7 Q. What was the subject of your reading then? 8 A. The subject was what kind of questionnaires you 9 administered to patients that determined the state of their 10 depression and so on. Or there were then several forms which 11 psychiatrists had developed for use in this kind of study. 12 Q. You've not seen or used any of those forms, 13 though, had you, Doctor Slater, prior to going hired in 1978 14 to revive the clinical trials on fluoxetine? 15 A. I don't think cats could respond to them. 16 Q. So the answer to my question is, you had not 17 seen any of these human questionnaires that would be 18 administered to humans involved in clinical trials, had you? 19 A. No, not prior to undertaking this 20 responsibility. 21 Q. Before this you had never administered any of 22 these tests to humans to see whether or not their depression 23 was getting better or worse, had you? 24 A. No. 25 Q. You didn't know how to do that, either, did you? 219 1 A. No. But I didn't know how to do cat studies 2 before I started doing them, either. 3 Q. Did you learn how to administer these 4 questionnaires and these psychiatric tests to subjects 5 participating -- human subjects participating in the clinical 6 trial? 7 A. I didn't attempt to make myself able to do the 8 trials, administer the questionnaires, but I did develop 9 knowledge sufficient to feel comfortable in discussing results 10 with investigators who were capable of administering them. 11 Q. But you are a result-oriented researcher as 12 opposed to a psychiatrist that went out and actually did the 13 clinical trials; is that correct? 14 A. Yes. 15 Q. In these clinical trials that you were going to 16 be doing with fluoxetine, the hands-on work and actual 17 observation of the patient was going to be done by one of the 18 investigators, wasn't it? 19 A. Yes. 20 Q. You didn't have any idea really, did you, Doctor 21 Slater, how to make a psychiatric observation in connection 22 with respect to whether or not an individual's depression was 23 becoming worse or better, did you? 24 A. Well, I think that I had done enough reading so 25 that I would be able to intelligently evaluate the 220 1 significance of a report from a competent psychiatrist. 2 Q. I understand that. 3 A. But I personally was not a psychiatrist. 4 Q. And as far as you being able to administer these 5 tests, you couldn't? 6 A. Probably not, but I'm not sure. 7 Q. I'm not trying to be critical of you, Doctor, 8 but your specialty was different? 9 A. Yes. 10 Q. You were not a psychiatrist, were you? 11 A. Yes. 12 Q. And, frankly, you didn't have any idea how to 13 administer a Hamilton depression scale test to a patient, did 14 you? 15 A. I think you're putting it a little bit more 16 broadly. I'm not quite that arrogant -- 17 MR. STOPHER: No. Ignorant? 18 A. Ignorant. I'm not quite that ignorant. 19 Q. You knew what the questions were? 20 A. I knew what the questions were, I knew what the 21 scales purported to show and how in the literature these were 22 evaluated. 23 Q. But as far as coming to a clinical diagnosis 24 with respect to any particular individual concerning whether 25 or not their depression was getting better or worse, you 221 1 weren't trained to do that, were you? 2 A. I was not trained. 3 Q. And didn't do it and couldn't do it, could you? 4 A. The scales purport to show improvement or 5 worsening by the numbers that come out of the scale and where 6 the numbers come from. I felt competent to say that if the 7 scale in the opinion of the psychiatrist seemed to show no 8 effect because there were no changes, I could answer that. If 9 they seemed to show substantial improvement because of changes 10 in scale, I could look at the scale and say this looks like an 11 honest interpretation of the data, and if they had shown 12 worsening of the thing, I think I would have felt competent to 13 do that. So I was not an ignorant dolt suddenly. 14 Q. And that's not the implication of my question, 15 Doctor Slater. My point simply is that for instance the 16 Hamilton Depression Scale is reported as a total of an 17 arithmetic scale, is it not? 18 A. Yes. 19 Q. But to put any particular numbers to any 20 particular area of the 21 or 29 different areas that the Ham D 21 evaluates, you were not trained to score any particular area; 22 correct? 23 A. All right. 24 Q. Is that correct? 25 A. Yes. 222 1 Q. In fact, you had never heard of the Hamilton 2 Depression Scale before you were asked in 1978 to revive the 3 clinical trials on fluoxetine? 4 A. Probably not, but I did not remember. 5 Q. You had never heard of the COVI insight scale? 6 A. No. 7 Q. You had never heard of the patient's global 8 impression as part of any psychiatric examination to determine 9 whether or not a patient was becoming more or less depressed, 10 had you? 11 A. Probably not. 12 Q. From 1976 until late 1978, when Doctor Shulman 13 was conducting the fluoxetine trials, were you reviewing that 14 work as it was being done, those clinical trials? 15 A. No, not to my recollection. 16 Q. Were you aware of the status of those clinical 17 trials at any particular time? 18 A. Not really. 19 Q. Before you were asked by Doctor Shedden in late 20 1978 to take over the fluoxetine trials, were you a member of 21 the fluoxetine team? 22 A. Yes. 23 Q. All right. In what respect? 24 A. I had been actively participating in the 25 discussions and were doing cat experiments and all the things 223 1 that I have described. 2 Q. We have some fluoxetine meetings is the reason I 3 was asking. You were on those fluoxetine team meetings 4 beginning in 1976, I think. 5 A. Now that you used the term fluoxetine team, I 6 have to say, one, that I don't remember because the term team 7 may have a different implication because when the company sets 8 up a project for clinical trials, a group of investigators who 9 had -- would participate in the supervision, somebody from 10 pharmaceutical development, somebody from analytical, somebody 11 from pharmacology, somebody from the clinic and so on would 12 constitute the team, and I do not remember being a formal 13 member of that particular team. If we refer to the team in 14 the more general sense that we're a team of people interested 15 in this project, then I was a member of that group, but out of 16 the formal research. Is that clear? 17 Q. Sure. And I thank you for expanding on that. 18 Have you seen the final reports or the results of Doctor 19 Shulman's clinical trials? 20 A. No. 21 Q. You simply knew that the result was that it 22 failed to demonstrate efficacy from fluoxetine in treating 23 depression; is that right. 24 A. Yes. 25 Q. I need for you to review with me what you did to 224 1 get a plan of a clinical trial started through the use of a 2 protocol. What was the first thing you did to secure a 3 protocol to run one of these clinical trials? 4 A. That's almost -- well, it's about 17, 18 years 5 ago, and to answer accurately it's beyond me. I think that we 6 did was review the various scales that you have mentioned, 7 decided which ones would like to use and what information, 8 ancillary information, to the scale we would like the 9 investigators to report to us, and with that type of thing, I 10 think we wrote protocols. And I have no clear recollection of 11 writing the protocol, but I suspect I did, and I suspect I 12 discussed it with the people in the medical group who had more 13 experience in writing protocols and with the people in the 14 fluoxetine group who were interested in this kind of thing. 15 That's the best I can do. 16 Q. When you say we, we reviewed scales, we selected 17 scales and we secured ancillary information, who are you 18 referring to in connection with we when you say we? 19 A. The people who I considered to be my friends and 20 colleagues, Doctor Fuller, Doctor Stark, Doctor Molloy and the 21 people in the supervision in the medical group. I don't think 22 I discussed them in detail with Doctor Shedden, but Doctor 23 Bendush was the man to whom or from whom I actually got the 24 money. 25 Q. Doctor Bendush -- 225 1 A. Yes. 2 Q. -- was the man from whom you got the money? 3 A. He was the one who was the man between Doctor 4 Shedden and the -- in the mechanics of setting up these 5 because his responsibility was for collecting such 6 information. 7 Q. Doctor Bendush was the one that approved the 8 funding for the study? 9 A. Uh-huh. 10 Q. Is that a yes? 11 A. Yes. 12 Q. Then who made the final decision with respect to 13 the particular protocol that was to be used in these studies? 14 MR. FOLEY: I'm out of line here. Did you go to 15 Line 23. 16 MR. SMITH: Page 116. 17 MR. FOLEY: Line 10? 18 MR. SMITH: Yeah. 19 MR. FOLEY: Yeah. 20 MR. SMITH: You want to read it again? 21 Q. Then who made the final decision with respect to 22 the particular protocol that was to be used in these studies? 23 A. I did. 24 Q. Did you submit that protocol to review by 25 anybody that was in a supervisory capacity? 226 1 A. Almost certainly, but I don't remember. 2 Q. Can you tell me who that would have been? 3 A. That would have been Doctor Bendush and Doctor 4 Shedden and so on. 5 Q. We know there were three investigators that were 6 hired. 7 A. Yes. 8 Q. Were there three separate studies done with 9 three different protocols? 10 A. I think the same protocol was more or less for 11 each of the investigators, but I wouldn't swear to that. 12 Q. Did you remember whether or not a placebo was 13 raised in the three studies? 14 A. The initial studies were open without placebo 15 but some of the studies did include the use of placebo later. 16 Q. I'm talking about those studies which you had 17 supervisory capacity. 18 A. Yes. There were some placebo-controlled 19 studies. 20 Q. Do you remember whether they were blind or 21 double-blind? Single-blind or double-blind, I guess that's 22 how you say it. 23 A. No. 24 Q. No, they were not blinded or you don't recall? 25 A. I don't remember. If I had to guess I would 227 1 guess they were single-blind and that the physicians knew but 2 not the patients. 3 Q. Do you recall whether or not there were 4 comparitor drugs used? And by that I mean whether fluoxetine 5 was compared with other antidepressants. 6 A. Only in the sense that all the patients had had 7 many other drugs before to which they had not responded. 8 Q. Some members of the group were getting 9 fluoxetine and other members of the group might be getting 10 Imipramine or things of that nature? 11 A. No. That was not the nature of my assignment as 12 I indicated several times. 13 Q. Was it your impression that these were patients 14 that were currently being treated by these investigators for 15 the mental illness of depression or were these patients that 16 the investigator went out and secured? 17 A. Some of each. 18 Q. Do you recall whether or not it was specified in 19 any of the protocols the duration for which the patients 20 should have been suffering from the illness? 21 A. No. 22 Q. And by that I mean whether or not the person had 23 been treated for depression or experienced depression for six 24 weeks, six months or six years? 25 A. I don't recall. 228 1 Q. Do you have an opinion with respect to whether 2 or not that would make any difference in the outcome of the 3 clinical trials, that is, the duration of the individual's 4 illness? 5 A Yes, I think so. If you had a patient who 6 had failed to respond to with three other antidepressants, the 7 probability of responding to a fifth or sixth one would be 8 substantially less than if it were a patient who had been 9 depressed but never treated with a drug because for obvious 10 reasons. 11 Q. How many patients were involved in these 12 clinical trials, if you recall? 13 A. I can't be sure, but I think the idea was that 14 each of them would probably do about ten patients, five to ten 15 patients. 16 Q. Why was the study limited to five to ten 17 patients? 18 A. It was hoped that we would be able to reach a 19 marginal decision on the basis of that kind of number. 20 Q. Did you check with any of the statisticians 21 there at Lilly to determine whether or not five -- a study 22 involving five or ten patients would be sufficient to 23 determine efficacy of fluoxetine for treatment of depression? 24 A. I didn't need a statistician to tell me that 25 five or ten patients would not be an adequate number to 229 1 establish efficacy. It was obvious all we were going to 2 accomplish was to answer the question should we do such a 3 study or accept the fact that this was a dud. 4 Q. Your purpose in doing your protocols and doing 5 your studies was not to get to the ultimate issue of whether 6 or not fluoxetine was efficacious in treating depression, but 7 whether or not there was -- you could generate enough data to 8 even go toward that question any further; is that correct? 9 A. Right. Correct. 10 Q. Doctor Slater, I would like to go back to there 11 paper you wrote which we're going to mark as Exhibit 1 in 12 connection with your experiment on cats and their REM sleep; 13 correct? 14 A. I haven't read that paper in ten years and I 15 just pulled it out of the file last night. 16 Q. All right. I would to read with you a 17 particular paragraph in that. I don't mean to hover over you, 18 but I want you to follow along with me in my reading and make 19 sure I read it correctly. I will be reading from Page 385 20 from your article, Inhibition of REM Sleep by Fluoxetine, a 21 Specific Inhibitor of Serotonin Uptake. It was published in 22 Neuropharmacology, Volume 17. Turning to Page 385, you say, 23 "After the cats had been receiving drug treatment for a few 24 days, it was noticed that their pupils were dilated but still 25 responsive to light. The degree of mydriasis seemed to be 230 1 dose related. By the fourth day of drug treatment, the cats 2 receiving the larger doses" -- and that's of fluoxetine; 3 correct? 4 A. Uh-huh. 5 Q. -- "which had been friendly for years began to 6 growl and hiss. They became distinctly unfriendly, but with 7 careful handling it was possible to administer the drug in the 8 usual way. The cats seemed to see clearly and did not seem to 9 be hallucinating. They became less irritable at the end of 10 the second week of drug administration. After cessation of 11 the drug treatment, the cats returned to their usual friendly 12 behavior in a week or two; those on higher doses recovering 13 more slowly. The severity of the behavioral change was dose 14 related being more severe and lasting longer in the cats 15 receiving the highest dose." Did I receipt that correct, 16 Doctor? 17 A. Yes. 18 Q. And does that accurately -- what you wrote there 19 accurately reflect at least part of your findings in 20 connection with the rat study, it's -- I mean, the cat 21 studies where you gave the cats fluoxetine? 22 A. Yes. 23 Q. Did you ever do any experiments or any studies 24 to ascertain whether or not any other animals would become 25 angry and exhibit these behavioral changes -- 231 1 A. No. 2 Q. -- when administered fluoxetine? 3 A. No. 4 Q. As I understand it, you have kept a diary of 5 sorts in connection with your work at Eli Lilly and Company? 6 A. Yes. 7 Q. And that that diary contains notations with your 8 work on Prozac or fluoxetine; is that right? 9 A. Yes. 10 Q. We have been handed in response to a subpoena a 11 document with 54 pages that purports to be a copy of that 12 diary; is that right? 13 A. Yes. 14 Q. But it's not a complete copy? 15 A. Right. 16 Q. Is it? 17 A. It contains as far as I can figure out all the 18 information related to fluoxetine. 19 Q. But it's not all of the information out of your 20 diary; is it? 21 A. No, of course not. 22 MR. SMITH: Let's mark that as Exhibit 2, which 23 I believe, Your Honor, is the exhibit that's already been 24 offered. 25 JUDGE POTTER: It is. 232 1 Q. Doctor Slater, I'm going to hand you and ask you 2 to look at Exhibit 2 and I'll ask you to identify that as a 3 Xerox copy of your diary? What was your habit in connection 4 with diary notations in your diary? 5 A. Well, the original notes says that every time I 6 have a difference of opinion with people and they don't do 7 what I tell them, it usually turns out badly and that I ought 8 to write things down to determine whether indeed I was right 9 as often as I thought. And, oh, wherever something came up 10 where I thought I would like to know what I was thinking about 11 at that time for later review, I put it in the diary. There 12 are a lot of personal things in the diary about other 13 projects. There are some things about some of my friends who 14 were having problems wanting divorce -- two divorces actually, 15 and that sort of thing where I predicted to myself what I 16 thought was going to happen to the separated people, what I 17 thought was going to happen because of this drug study and 18 that drug study. It contains a large variety of nonsense. 19 Q. You didn't make daily notations? 20 A. No. And there are very many important things 21 which are not in the diary. 22 Q. But the primary emphasis for you making a 23 notation in your diary would be that if you wanted to recall 24 something that was said and be able to pull back your thoughts 25 on what was expressed to you at the later date, you would have 233 1 a written record of that? 2 A. Yes. 3 Q. How long have you been keeping a diary or log 4 such as this? 5 A. I think the initial entry is 1958. 6 Q. How long did you continue to keep the diary? 7 A. There are some notations that go to last year. 8 Q. 1993? 9 A. Uh-huh. Which are obviously unrelated to 10 fluoxetine. 11 Q. Would you normally keep this diary at home and 12 make notations in it at home or would you carry it with you? 13 A. It was in my desk at work and I never took it 14 home until I had finished the volume. There were three 15 volumes and when I finished the volume I took it home and it's 16 been sitting in the guest room closet mostly unread. 17 Q. Did you go through your diary in connection with 18 your deposition here to refresh your recollection? 19 A. I told you that I had. 20 Q. Did you need it to refresh your recollection 21 concerning events with respect to your work on fluoxetine? 22 A. Yes. After all, it's been 20 years and I don't 23 remember every detail. There's some things that I remembered 24 and some things I said "Oh, my gosh." 25 Q. I need to get some of these abbreviations, also. 234 1 It looks like the first notation that might have to do with 2 fluoxetine is November 12, 1970; is that correct? 3 MR. FOLEY: What line are you on, Paul? 4 MR. SMITH: Page 132, beginning Line 9. Do you 5 want me to repeat the question? 6 MR. FOLEY: No. "Answer: Yes." 7 Q. And for review, you were director of 8 pharmacological research with Lilly in November of 1970?? 9 A. I think so. 10 Q. The first notation says extended meeting of CNS 11 core committee, and you need to look at these notes, too, and 12 see that I'm reading correctly. 13 A. Uh-huh. 14 Q. And what do you mean by CNS? 15 A. Central nervous system. 16 Q. Would that be a drug in which fluoxetine would 17 fall? 18 A. That would be a field of research. 19 Q. It says stark, Rathbun, Molloy, Slater and 20 Fuller; correct? 21 A. Yes. 22 Q. There's the next notation on Page 6, February 2, 23 '73, it says left pen at home? 24 A. Yes. This is in a different pen, yes. 25 Q. Yesterday I began a campaign to get 82816,our 235 1 specific 5-HT uptake inhibitor into the clinic soon. Nobody 2 seemed ready to risk -- 3 A. Rush. 4 Q. Rush (i.e. Fuller, Molloy or Stark) I think our 5 present data are sufficient for a go decision. And I can't 6 read what the next word is. 7 A. No additional negative result will negate 8 decision but a large body of additional data will be 9 collected. 10 Q. All right. And compound 82816 is what, Doctor? 11 A. It's the oxalate salt and fluoxetine is a 12 hydrochloride. 13 Q. And the fluoxetine oxalate salt and fluoxetine 14 hydrochloride are both chemically and physiologically 15 fluoxetine? 16 A. Yes. But you can't give oxalate salt to people. 17 Q. Why is that? 18 A. I think oxalate is a toxic substance, so it was 19 clear that we would have to use a different salt. 20 Q. But 82816 is the new drug that became 21 fluoxetine; is that right? 22 A. Yes. In a sense. 23 Q. And there you say, I think our present data are 24 sufficient for a go decision. No additional negative result 25 will negate the significance but a -- is that large body of 236 1 significant data will be selected? 2 A. Uh-huh. 3 Q. What do you mean there when you say no 4 additional negative data will negate the decision? 5 A. I meant data that showed a lack of activity in 6 any additional tests. 7 Q. So there wouldn't be anything -- I'm still not 8 understanding? 9 A. Clearly any toxic data would cause the compound 10 to be set aside but negative data which implied that it was a 11 remarkable psychiatric drug in animals would change my feeling 12 that we probably had an antidepressant. 13 Q. Can we say there by virtue of your notations 14 there that in February of 1973 you became convinced that 15 fluoxetine hydrochloride would be an effective antidepressant? 16 A. No. I think we can say that I was convinced 17 that it was a compound worthy of being tested as a possible 18 antidepressant, which is a little different. 19 Q. The next notation on Page 7 is indicated 20 4-10-73. Can you read that for us? 21 A. It says 82816 (110140) reduced REM sleep in five 22 of six cats, the sixth had almost none to start, doses of two 23 and a half to five milligrams, reserpine increases PGO spikes. 24 Q. What are PGO spikes? 25 A. I think pontogeniculate, if I remember. I used 237 1 to be an expert in the sleep business, but that was a long 2 time ago. 3 Q. A PGO spike is something you see? 4 A. It's an electroencephalographic wave with a 5 sharp margin, a sharp pattern. 6 Q. Here where you're talking about the REM sleep in 7 the five or six cats, is this the same experiment that is the 8 subject of your article? 9 A. Yes. This is the beginning. 10 Q. Turn to Page 8, and can you read that notation, 11 6-11-73? 12 A. Parachloramphetamine causes long lasting, two to 13 three month decrease in brain serotonin level. 14 Q. What is parachloramphetamine? I didn't say that 15 right. 16 A. Parachloramphetamine is an amphetamine with the 17 chlorine molecule in the imperial position and it is a 18 substance which decreases brain serotonin levels. It's not a 19 marketed drug, I don't think. It must be an appetite 20 suppressant, but I don't know if it is. 21 Q. Were you using this? 22 A. Doctor Fuller was using this as a tool. 23 Q. All right. Go ahead and read the rest of it. 24 A. When 110140 is administered 3, 6, 24 or 48 hours 25 after parachloramphetamine, the 5-HT decrease is reversed, 238 1 but fluoxetine at 7 days does not alter the decrease when rats 2 were killed on Day 8. Could there be a lack of binding sites 3 and would 5-HT still be down at Day 9 and 10 and so on. 4 Fuller may look into this. The major idea here is Ray's, 5 which is Doctor Fuller, I suggested a two- or three-day wait. 6 Q. All right. Doctor, since I'm not a doctor or a 7 chemist or scientist, can you explain to me what we're talking 8 about in this notation of June 11th, 1973? I need your help 9 in telling me what you're discussing. 10 A. Since it's 15 years, I probably need Doctor 11 Fuller's help, but this is related to the mechanics of 12 serotonin uptake and the fact that parachloramphetamine is 13 presumably using the same mechanism or affecting the serotonin 14 levels in the brain and determining what the consequences of 15 affecting serotonin uptake. 16 Q. Do you have a general sense of what the 17 significance of this notation was? 18 A. The significance is that the compound works not 19 only in isolated systems, such as Doctor Wong had done, but 20 seems to work in intact animals. 21 Q. All right. Your notation of 10-11-73 has to do 22 with 94939 and so does your 12-14-73 notation. Then on Page 23 12, you note on 1-18-74, that increasingly I am concerned 24 about urinary retention with 110140. Is that Dick Moore? 25 A. Uh-huh. 239 1 Q. First noticed that our 24-hour cats often failed 2 to urinate overnight. Tust report that one new dog collected 3 215 milliliters in her bladder. Molloy suggested that -- 4 A. Tust. 5 Q. -- Tust check this in rats. The last five-hour 6 run does not suggest retention. And I can't read that last 7 sentence. 8 A. We may have to do cystograms. 9 Q. Did you ever determine whether or not fluoxetine 10 caused urinary retention in animals or humans? 11 A. I never did in humans and we had the data from 12 the cats which are described here and we didn't see it in 13 rats. 14 Q. Does fluoxetine have amphetamine-like activity? 15 A. No, I don't think so. It depends on how you 16 define amphetamine activity. But I can't say, the only one, 17 people eat less after amphetamine and many people eat less 18 after fluoxetine. 19 Q. Amphetamines are generally stimulants, also, 20 aren't they, Doctor? 21 A. Amphetamine is a stimulant. 22 Q. And fluoxetine acts as a stimulant in many 23 individuals, does it not? 24 A. I don't think so, but I really don't know. 25 Q. Well, it had a stimulating effect on the cats, 240 1 didn't it? 2 A. It made the cats somewhat irritable. It may 3 have been the distended bladder for all I know. 4 Q. Turn to Page 19 with me, Doctor, to your 5 notation of 1-16-76. There's talk there about compound 99638 6 and 94939. What is the relationship of these notations and 7 these compounds to fluoxetine? 8 A. Oh, the relationship of the first paragraph is 9 none. The relevant information is, talked with Bennett, 10 Fuller, Molloy and Rathbun yesterday about J Small's study of 11 ten patients on 94939. We were all puzzled by the high 12 incidence of tremor. Our question is whether some were 13 extra-pyramidal reaction. Both Bennett and Lemberger have 14 lined up possible investigators, it looks like 2000 patients 15 for 4 weeks. One patient, an obsessive-compulsive, showed 16 really remarkable improvement, but all the patients were drug 17 refractory. 18 Q. Who is Bennett? 19 MS. ZETTLER: It's marked out pursuant to court 20 order. 21 Q. Who is Bennett? 22 A. Irvin Bennett is a psychiatrist hired by Eli 23 Lilly and Company. I think he died last year. 24 Q. And he was employed at Eli Lilly and Company? 25 A. Yes. 241 1 Q. Read the 9-8-76 notation on Page 21. 2 A. Twenty-one? 3 Q. Yes. 4 A. Talked with Marsden and Kiplinger about Bennett, 5 94939 and report forms. The current delay results from 6 preparation of forms which is essential for starting. This I 7 do not understand. Talked with Fuller to say that if 8 Lemberger is not interested in acting as monitor on 110140, 9 then he, Molloy, or I will have to take over. We had become 10 discouraged with the pace that doctor Bennett was able to 11 generate. 12 Q. All right. You and Molloy and Lemberger -- 13 A. Uh-huh. 14 Q. -- and Fuller were discouraged with the pace 15 that Doctor Bennett, the psychiatrist, was moving? 16 A. On the 94939. 17 Q. But you mentioned 110140, fluoxetine, also? 18 A. We were about at the stage where we were 19 beginning to think about the clinical trial of this compound 20 and Doctor Bennett had additional responsibilities. It was 21 our judgment that the research would not move forward at a 22 reasonable pace under Doctor Bennett's supervision. 23 Q. All right. Did Doctor Bennett ever 24 participate -- 25 A. Not to my knowledge. 242 1 Q. -- in any clinical trials on fluoxetine? 2 A. Not to my knowledge. 3 Q. Was Doctor -- 4 A. Doctor Shulman. 5 Q. -- Doctor Shulman the first physician to 6 participate in the clinical trials? 7 A. Yes. Well, Doctor Lemberger did the Phase 1 8 studies. 9 Q. But the first clinical trials on humans were 10 done by Doctor Shulman? 11 A. Well, Phase 1 studies are clinical trials. 12 Q. Okay. But they're not depression -- the 13 patients are not depressed? 14 A. Right. 15 Q. Did you talk with anybody else other than Doctor 16 Fuller concerning you're disappointed with Doctor Bennett and 17 his performance in the clinical trials on these other 18 compounds? 19 A. I don't remember. 20 Q. It looks like 10-10-78 is when you were first 21 approached concerning the fluoxetine clinical trials? 22 A. Doctor Fuller apparently asked me. I don't 23 remember this conversation but here it is. 24 Q. It says, Ray Fuller asked when I would be 25 willing to take over the clinical monitorship of fluoxetine 243 1 when Bob Shulman leaves. I said I would not volunteer but, if 2 asked, I would. Correct? 3 A. Correct. 4 Q. Can you read the notation of 10-26-78? 5 A. If 5-HT agonist effects contributes to LSD 6 induced limb flicks, would fluoxetine enhance flicks or reduce 7 dose. 8 Q. All right. What are LSD induced limb flicks? 9 A. A guy at Princeton whose name -- he's Barry 10 somebody, published a paper in brain research which said that 11 cats treated with relatively large doses of LSD-25 developed a 12 peculiar pattern of flicking their paws and he attributed that 13 to a synergic mechanism, and I was wondering if indeed this 14 was a synergic mechanism, how would fluoxetine affect it. I 15 don't think we ever did the experiment. 16 Q. You didn't notice this LSD flick in the cats 17 that you administered fluoxetine to? 18 A. No. We did a fairly long series of studies on 19 limb flicks because we were looking at pergolide at the time. 20 Q. At what. 21 A. Pergolide, which is a drug used for treatment of 22 Parkinsonism, but I don't think it's worthwhile going into 23 these, and I don't agree with Doctor whatever his name was, 24 Barry something, that this is a specific test for anything. 25 Q. Is it your testimony that LSD, its psychotropic 244 1 effect is on the serotonin system? 2 A. Not mine. That's out there, there's some -- LSD 3 effects in this particular assay occur at doses that are 4 larger in milligrams per kilo in cats than in the doses, total 5 doses given to man, and produce all the hallucinations, man 6 will have hallucinations with a fraction of a milligram of 7 LSD, and it takes at least that much milligram per kilo in a 8 cat to induce limb flicks. And you can induce limb flicks in 9 cats with a large variety of alkaloids at comparable doses and 10 these compounds are in clinical use all the time for a variety 11 of things like treating postpartum hemorrhage, treating 12 migraine and so on, and do not at modest doses cause 13 hallucinations. There's no question that there are a lot of 14 drugs that in very large doses will cause hallucination. 15 Q. We're speaking of LSD or when you're speaking of 16 LSD are you using that term like we pick up a Time Magazine? 17 A. Yes. 18 Q. So a resurgence of LSD, I wouldn't -- is the 19 effect, the hallucinatory effect that LSD is having on me, is 20 that affecting my serotonin system in my brain or is it 21 affecting my Dopamine system? 22 A. I really don't know. It's occurring at such 23 small doses it's very hard to be sure. 24 Q. At large doses it's affecting the serotonin 25 system in cats, you know that? 245 1 A. Yes. 2 Q. Yes, under the 12-21, it looks like there's a 3 12-t22 notation. 4 A. Managed to get protocol proposals to both, 5 blank, and Bendush thinks fluoxetine is partway down the tube 6 and doesn't want to spend $4,598 for one patient with 7 narcolepsy. 8 Q. And who was Bendush at this time? 9 A. Bendush was the man between me and Doctor 10 Shedden. He was in charge of medical affairs. 11 Q. Did you and -- you and Doctor Bendush ever 12 discuss why he felt that fluoxetine was partway down the tube 13 at that time? 14 A. This was his judgment based on Doctor Shulman's 15 recommendation. 16 Q. Do you know if a Doctor Shulman ever wrote a 17 formal memorandum or report formally recommending that the 18 clinical trials on the fluoxetine be abandoned? 19 A. I do not. 20 Q. The next notation is 1-29-79? 21 A. Yes. 22 MR. SMITH: Your Honor, that completes the 23 portions that we had with limb flick and things of that 24 nature. 25 JUDGE POTTER: This would be a good time to take 246 1 the evening break. Ladies and gentlemen, we're going to take 2 the evening break. I know it's kind of hard for you to keep 3 your interest up when we're reading all this stuff, but it 4 seems like you're making a good effort. I want to remind you 5 that tomorrow is 9:00 when -- we'll start at 9:00 tomorrow. 6 I'm going to give you the same admonition I've given you 7 before. Do not allow anybody to communicate with you on any 8 topic connected with this trial and that includes your 9 friends, your relatives, people who are just curious. Not 10 only don't talk about the case but don't talk about any topic 11 connected with the trial. The same goes for getting 12 information off the news media, whether it be the newspaper, 13 television, or radio or whatever. Also do not discuss the 14 case among yourselves and do not form or express opinions 15 about it. We'll stand in recess till 9:00 tomorrow morning. 16 (JURORS EXCUSED AT 4:45 P.M.) 17 JUDGE POTTER: Since your backup troops aren't 18 here, I'm going to give this to you. These are today's 19 exhibits. Mr. Myers, I assume there's no objection to adding 20 all these things into evidence; they were given to the jurors. 21 MR. MYERS: No objection. 22 JUDGE POTTER: We're talking 32 through 40 on 23 Doctor Fuller and 41 on Doctor Slater. And we'll redo the 24 list so it adds up. Is there anything we need to take up 25 before tomorrow morning? Why don't I take a half hour and 247 1 you-all take your last wheedle at quarter after five and that 2 will give her a chance to dump her machine. Even though we 3 don't have him on the list, we understand that Doctor Thompson 4 is going to be leaving town next week for a couple of weeks; 5 we'd like to take him Wednesday or Thursday of this week. 6 You-all talked about that last time. 7 MR. MYERS: Wednesday or Thursday. Not 8 tomorrow, though. 9 MS. ZETTLER: No. 10 MR. MYERS: That's all right. 11 MS. ZETTLER: We've narrowed it down, Judge. 12 MR. MYERS: 183. 13 MS. ZETTLER: 183, he wants Lines 3 through 17 14 out. 15 JUDGE POTTER: Reverse play. 16 MR. MYERS: Our position on that, Judge, is that 17 there is just no admissible evidence of that fact; it's sort 18 of like are-you-still-beating-your-wife-type question. 19 JUDGE POTTER: Are you going to get evidence in? 20 MS. ZETTLER: We're going to get evidence in 21 that he has a reputation for doing that. 22 JUDGE POTTER: Okay. Sustain that one. 23 MR. MYERS: 286. 24 JUDGE POTTER: It's my interest to see this 25 thing move along so you can take what I say with a grain of 248 1 salt, Ms. Zettler, but you might go up and check with the 2 video people to see if -- and I don't know how much of this 3 you dropped out but you might check with them to see what kind 4 of -- use them as a shadow jury to see if maybe even more 5 cutting might be beneficial but that, you know... What is it 6 on 286? 7 MR. MYERS: There was an answer and then an 8 explanation or a nonresponsive response depending on who is... 9 JUDGE POTTER: Okay. Let me get it. Are we 10 still reading from a diary in here? 11 MS. ZETTLER: Part of it is. 12 MR. MYERS: It's interspersed. 13 JUDGE POTTER: Okay. 14 MS. ZETTLER: That's just gratuitous and 15 nonresponsive. 16 MR. MYERS: Our position is it's part of the 17 answer. 18 MS. ZETTLER: He's talking about a finite period 19 of time; he's not talking about what followed. 20 JUDGE POTTER: Explain to me again, Ms. Zettler, 21 what this series is designed to prove, that 60 causes 22 agitation, right, that figured that out at the time? 23 MS. ZETTLER: Just that the agitation occurred 24 but they were saying the 60, yes, causes a lot of agitation. 25 JUDGE POTTER: And we all -- does everybody 249 1 agree that there's later studies that show that 60 causes 2 agitation? 3 MS. ZETTLER: No. That's not what that means. 4 What he's saying there is there are other detailed studies 5 that followed that. What Paul is trying to establish is at 6 that time with those studies there was. 7 JUDGE POTTER: I'm going to let it come in. 8 MR. MYERS: All right. The next, Judge, is a 9 series of objections all along the same line at pages -- 10 running from Page 295 to 324. The general subject matter is 11 Doctor Slater was questioned about some information that he 12 had gotten from my partner, Mr. Lore, and then there was a 13 line of questioning that followed that: "Did you get this 14 information from Lilly's lawyers, did you get this information 15 from Lilly's lawyers," and we just think the form of the 16 question is inappropriate because he could have been asked if 17 he was aware of the information, but it's not relevant as to 18 whether he got it from Mr. Lore or from me or from any other 19 lawyer. 20 JUDGE POTTER: You say it starts on 295? 21 MR. MYERS: 295 to 394. 22 MS. ZETTLER: 295 is where he said -- I think 23 what you're objecting to there is -- 24 JUDGE POTTER: At the hospital? 25 MS. ZETTLER: Right. Do you know where the guy 250 1 was located? 2 MR. MYERS: Right. And it sort of took off 3 after that. 4 MS. ZETTLER: Uh-huh. Let me do it. 5 JUDGE POTTER: Just out of clearness, take out 6 where -- I don't think I'm supposed to tell. Lines 20, 21 7 and 22. I mean, that's just an aside. 8 MR. MYERS: All right. 9 JUDGE POTTER: Who is the "he" in this? 10 MS. ZETTLER: He's the doctor that we don't know 11 who he is because his name is blocked out. 12 JUDGE POTTER: One of the -- 13 MS. ZETTLER: Investigators. 14 JUDGE POTTER: -- clinical investigators. All 15 right. (Reviews document) Didn't we kind of come to some kind 16 of agreement on some of this pretrial stuff that the witnesses 17 perhaps were not going to be subject to... 18 MS. ZETTLER: Can I give you a little background 19 on what this guy is talking about? There were two patients in 20 one of the early clinical trials and these are the two 21 patients we're talking about. One became psychotic and 22 suicidal and the other became worse and was just called a 23 failure. As you can see, he volunteers at some point during 24 that testimony when we're asking him about the clinical report 25 forms that he contacted Mr. Lore, who is not his lawyer at 251 1 this time, and asked him to find out information about what 2 happened with these patients. Okay. Now, it's our position 3 that this shows what the significance of those two adverse 4 events were, at least in Doctor Slater's mind that he feels 5 it's necessary when he reads about it in his diary to call the 6 Lilly contact and try and find out more about what's going on. 7 MR. MYERS: In response to the Court's 8 question -- on the motion in limine. 9 JUDGE POTTER: Put the question aside. You've 10 convinced me that your testimony is that he sees something in 11 his diary that he thinks is fairly important or he doesn't 12 understand or he wants to follow up and calls the Lilly lawyer 13 and says get me the background -- get me the documents you got 14 surrounding whatever this is in my diary. 15 MS. ZETTLER: Right. 16 JUDGE POTTER: All right. I'm going to sustain 17 the objection. If you want to rewrite it, you know, that I 18 called someone and he checked the company records and these 19 things were indeed reported, we'll do it that way. If you 20 want in the fact that he thought this was important so he 21 bothered to get additional information in preparation for his 22 deposition, that's fine. I mentioned this note to someone and 23 he called Lilly and they checked the company records. I'm 24 really tempted to take it all out. 25 MS. ZETTLER: Why don't I take it out that it's 252 1 a Lilly lawyer? 2 MR. MYERS: I don't have any problem with the 3 testimony coming in, it's simply the person with whom the 4 contact was. 5 MS. ZETTLER: The jurors aren't going to know 6 who Mr. Lore is if we just leave in Mr. Lore. 7 MR. MYERS: He may make a surprise appearance 8 during the course of the trial. 9 MR. SMITH: He'll be the most surprised. 10 JUDGE POTTER: Let me have your nice dark black 11 pen. "So I mentioned this note to the company and they 12 checked the company records and these things have indeed been 13 reported." Is this with Mr. Lore? 14 MS. ZETTLER: Wait. Wait. Wait. Before you 15 take that out, I mean. Can't we just leave this in and take 16 out here Lilly reported to you that they called back? 17 MR. MYERS: I don't have a problem with that. 18 JUDGE POTTER: I think you're making a big 19 mistake. 20 MS. ZETTLER: Why do you say that? 21 JUDGE POTTER: These people have enough on their 22 minds without worrying about small stuff like this. 23 JUDGE POTTER: Does that take it out? 24 MS. ZETTLER: I believe so, Judge. I'll go 25 through it and edit it and make sure it's not... 253 1 MR. MYERS: That's fine. 2 MS. ZETTLER: And then one last item, 387. I'm 3 not so sure we didn't take that out, I need to see that again. 4 MR. MYERS: That's the one about the redaction. 5 MS. ZETTLER: Oh, okay. Now, the problem with 6 this, Judge, we have no problem agreeing with it, but Mr. 7 Myers has indicated he's going to make a hearsay objection to 8 that which he did not make here. 9 MR. MYERS: Not to the testimony, to the 10 document. 11 MS. ZETTLER: And I'm just saying I think 12 whether or not it's hearsay -- 13 JUDGE POTTER: Get me up to speed. What are we 14 talking about here? 15 MR. MYERS: This is the exhibit to which that 16 testimony refers. The questioning, as I understand it, is 17 about the redaction, Lines 6 to 20. 18 JUDGE POTTER: Wait. Wait. (Reviews document). 19 MS. ZETTLER: That's a letter by the 20 investigator who essentially was the guy who treated those two 21 patients we were talking about earlier. 22 MR. MYERS: We had talked, Your Honor, about on 23 Line 14 and thereafter striking out everything that references 24 the blacking out, but letting him answer the question where he 25 says no, but I just want to reserve any objection I've got to 254 1 the document. 2 MS. ZETTLER: He's talking about leaving in 3 "no." 4 MR. MYERS: And I just reserve my objection on 5 the document. 6 JUDGE POTTER: Okay. 7 MR. MYERS: That's it. 8 (OFF THE RECORD) 9 (PROCEEDINGS TERMINATED THIS DATE AT 5:28 P.M.) 10 * * * 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 255 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 256 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