1 NO. 90-CI-6033 JEFFERSON CIRCUIT COURT DIVISION ONE (1) 2 3 JOYCE FENTRESS, ET AL. PLAINTIFFS 4 5 VS. DEPOSITION FOR PLAINTIFFS 6 7 SHEA COMMUNICATIONS, ET AL. DEFENDANTS 8 * * * * * * * * * * 9 10 DEPONENT: DR. RAY W. FULLER 11 DATE: APRIL 14 AND 15, 1994 12 13 * * * * * * * * * * 14 15 16 REPORTER: KATHY NOLD 17 18 KENTUCKIANA REPORTERS SUITE 260 19 730 WEST MAIN STREET LOUISVILLE, KENTUCKY 40202 20 (502) 589-2273 Page 1 1 * * * * * * * * * * 2 3 UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF INDIANA 4 INDIANAPOLIS DIVISION 5 IN RE ELI LILLY AND COMPANY ) Prozac Products Liability ) MDL Docket No. 907 6 Litigation ) 7 * * * * * * * * * * 8 NO. 91-02496-A 9 JACKIE LYNN BIFFLE, ET AL ) IN THE DISTRICT ) COURT OF 10 V. ) DALLAS COUNTY, TEXAS ) 11 ELI LILLY & COMPANY AND ) 14TH JUDICIAL DISTA PRODUCTS COMPANY ) DISTRICT 12 * * * * * * * * * * 13 NO. 92-14775-E 14 RICHARD HAROLD CROSSETT, JR., ) IN THE 15 CHAD H. CROSSETT, AMY MICHELLE ) DISTRICT CROSSETT AND KRISTEN ANN CROSSETT, ) COURT OF 16 INDIVIDUALLY AND AS SURVIVORS OF ) AND ON BEHALF OF THE ESTATE OF ) 17 JOCQUETTA ANN CROSSETT, DECEASED ) ) 18 V. ) DALLAS COUNTY, ) TEXAS 19 ELI LILLY & COMPANY, DISTA ) PRODUCTS COMPANY, TEXAS ) 20 PSYCHIATRIC COMPANY, INC. ) D/B/A/ HCA WILLOW PARK ) 101ST JUDICIAL 21 HOSPITAL, JAMES K. WITSCHY, M.D., ) DISTRICT AND DOUG BELLAMY, ED.D. ) Page 2 1 * * * * * * * * * * 2 NO. A-921,405-C 3 MARIA GUADALUPE REVES ) IN THE 4 INDIVIDUALLY AND AS NEXT ) DISTRICT COURT FRIEND OF GRANT JULIAN REVES ) OF 5 A MINOR CHILD, AND ON BEHALF ) OF THE ESTATE OF CHRISTIAN ) 6 MARIE REVES, DECEASED ) ) ORANGE COUNTY, 7 V. ) TEXAS ) 8 ELI LILLY & COMPANY, DISTA ) PRODUCTS COMPANY, RAVIKUMAR ) 9 KANNEGANTI, M.D., HOSPITAL ) CORPORATION OF AMERICA, A ) 10 TENNESSEE CORPORATION, HEALTH ) SERVICES ACQUISITION CORP., ) 11 A DELAWARE CORPORATION, ) HCA PSYCHIATRIC COMPANY, A ) 12 DELAWARE CORPORATION, TEXAS ) PSYCHIATRIC CO., INC.. A/K/A ) 13 AND/OR D/B/A HCA BEAUMONT ) NEUROLOGICAL HOSPITAL, AND HCA ) 14 HEALTH SERVICES OF TEXAS, INC. ) 128TH JUDICIAL A/K/A AND/OR BEAUMONT ) DISTRICT 15 NEUROLOGICAL HOSPITAL ) Page 3 1 * * * * * * * * * * 2 3 IN THE CIRCUIT COURT OF COOK COUNTY, ILLINOIS COUNTY DEPARTMENT - LAW DIVISION 4 RENATO DI SILVESTRO, Individually ) 5 and as Special Administrator of ) the Estate of JOHN DI SILVESTRO, ) 6 Deceased, ) ) 7 Plaintiff, ) ) 8 v. ) No. 91 L 7881 ) 9 ROBERT L. NELSON, et al., ) ) 10 Defendants, ) ) 11 GEORGE MELNICK, M.D. and PETER ) FINK, M.D. ) 12 ) Respondents in Discovery.) 13 * * * * * * * * * * Page 4 1 2 SUPERIOR COURT OF THE STATE OF CALIFORNIA 3 FOR THE COUNTY OF LOS ANGELES 4 DR. MARIUS SAINES, etc., et al., ) Case No: ) SC 008331 5 Plaintiffs, ) ) 6 vs. ) ) 7 ELI LILLY & COMPANY, a corporation; ) DISTA PRODUCTS COMPANY, a division ) 8 of Eli Lilly & Company; and DOBS 1- ) 100, inclusive, ) 9 ) Defendants. ) 10 ____________________________________) 11 * * * * * * * * * * 12 NO. 93-8792-D 13 DAVID KUNG, DALE KUNG COHEN ) IN THE DISTRICT 14 ROBERT KUNG, AND TIMOTHY KUNG, ) COURT OF INDIVIDUALLY AND AS SURVIVORS ) 15 AND STATUTORY BENEFICIARIES ) OF MAY YUN KUNG, DECEASED ) 16 ) VS. ) DALLAS, COUNTY 17 ) T E X A S ELI LILLY AND COMPANY, DISTA ) 18 PRODUCTS COMPANY, AND MONIQUE ) KUNKLE, PH.D. ) 19 Page 5 1 * * * * * * * * * * 2 IN THE DISTRICT COURT OF JOHNSON COUNTY, KANSAS 3 CIVIL COURT DEPARTMENT 4 EUGENE HUSLIG, AS ADMINISTRATOR ) 5 AND EXECUTOR AND ON BEHALF OF ) THE ESTATE OF DEBORAH G. WEATHERS ) 6 HUSLIG, DECEASED, AND AS SURVIVING ) HUSBAND AND HEIR AT LAW OF DEBORAH ) 7 G. WEATHERS HUSLIG, DECEASED, ) AND IN HIS INDIVIDUAL CAPACITY AS ) 8 HUSBAND OF DEBORAH G. WEATHERS ) HUSLIG, DECEASED, AND RONALD C. ) 9 WEATHERS, SON OF DEBORAH G. ) WEATHERS HUSLIG, DECEASED, ) CASE NO.: 10 ) 94 C 192 PLAINTIFFS, ) 11 VS. ) COURT NO. 7 ) CHAPTER 60 12 MARY L. BILLINGSLEY, EXECUTOR OF ) THE ESTATE OF THAD BILLINGSLEY, ) 13 M.D., DECEASED D/B/A THE BENESSERE ) CENTER, SUSAN C. JOHNSON, PH.D., ) 14 BILLINGSLEY ENTERPRISES, INC., ) F/K/A THAD H. BILLINGSLEY, M.D. ) 15 CHARTERED, D/B/A THE BENESSERE ) CENTER, ELI LILLY AND COMPANY, ) 16 AND DISTA PRODUCTS COMPANY, ) ) 17 DEFENDANTS. ) 18 * * * * * * * * * * Page 6 1 * * * * * * * * * * 2 CAUSE NO. 93-04911-A 3 LINDA JILL WELCH, CARLINDA 4 WELCH REX, CONNAN ROSS WELCH AND CHAD MICHAEL WELCH, 5 INDIVIDUALLY AND AS SURVIVORS AND STATUTORY BENEFICIARIES 6 OF CARL EUGENE WELCH, DECEASED PLAINTIFFS 7 V. 8 ELI LILLY AND COMPANY, DISTA PRODUCTS COMPANY, NOE NEAVES, 9 M.D., AND MINITH-MEIER CLINIC, P.A. DEFENDANTS 10 Page 7 1 THE DEPOSITION OF DR. RAY W. FULLER, TAKEN 2 AT THE OFFICE OF BAKER & DANIELS, 300 NORTH 3 MERIDIAN STREET, SUITE 2700, INDIANAPOLIS, 4 INDIANA 46204, ON APRIL 14 AND 15, 1994; SAID 5 DEPOSITION TAKEN PURSUANT TO NOTICE IN ACCORDANCE 6 WITH THE RULES OF CIVIL PROCEDURE. 7 * * * * * * * * * * 8 A P P E A R A N C E S 9 10 NANCY ZETTLER COUNSEL FOR PLAINTIFFS 11 1405 WEST NORWELL LANE SCHAUMBURG, ILLINOIS 60193 12 PAUL SMITH 13 COUNSEL FOR PLAINTIFFS 745 CAMPBELL CENTER 2 14 8115 NORTH CENTRAL EXPRESSWAY DALLAS, TEXAS 75206 15 LAWRENCE J. MYERS 16 COUNSEL FOR ELI LILLY AND COMPANY FREEMAN & HAWKINS 17 4000 ONE PEACHTREE CENTER 303 PEACHTREE STREET, N.E. 18 ATLANTA, GEORGIA 30308-3243 19 MARGARET M. HUFF ELI LILLY AND COMPANY 20 LILLY CORPORATE CENTER INDIANAPOLIS, INDIANA 46285 21 JOHN F. BRENNER 22 MCCARTER & ENGLISH COUNEL FOR ELI LILLY AND COMPANY 23 FOUR GATEWAY CENTER 100 MULBERRY STREET 24 NEWARK, NJ 07102-4096 Page 8 1 ALLISON SPRUILL COUNSEL FOR BEAUMONT NEUROLOGICAL HOSPITAL 2 FRIEND & ASSOCIATES LLP 1301 MCKINNEY #2900 3 HOUSTON, TEXAS 77010 4 KAREN A. SEYMOUR COUNSEL FOR DR. BILLINGSLEY 5 WALLACE, SAUNDERS, AUSTIN, BROWN & ENOCHS 10111 W. 87TH ST. 6 P.O. BOX 12290 OVERLAND PARK, KANSAS 66282 7 ROBERT L. HARRIS 8 COUNSEL FOR NOE NEAVES, M.D. SIFFOLD & ANDERSON, LLP 9 6300 NATIONS BANK PLAZA 901 MAIN STREET 10 DALLAS, TEXAS 75202 Page 9 1 I N D E X 2 3 DEPOSITION OF DR. RAY W. FULLER 4 5 DIRECT EXAMINATION BY MR. SMITH 11 6 CROSS EXAMINATION BY MS. ZETTLER 228 7 REDIRECT EXAMINATION BY MR. SMITH 251 8 CROSS EXAMINATION BY MS. ZETTLER 347 9 10 CERTIFICATE 483 11 ERRATA 482 12 EXHIBITS 13 PLAINTIFFS' EXHIBIT NO. 1 157 PLAINTIFFS' EXHIBIT NO. 2 162 14 PLAINTIFFS' EXHIBIT NO. 3 165 PLAINTIFF'S EXHIBIT NO. 4 183 15 PLAINTIFFS' EXHIBIT NO. 5 213 PLAINTIFFS' EXHIBIT NO. 6 220 16 PLAINTIFFS' EXHIBIT NO. 7 317 PLAINTIFFS' EXHIBIT NO. 8 333 17 PLAINTIFFS' EXHIBIT NO. 9 360 PLAINTIFFS' EXHIBIT NO. 10 367 18 PLAINTIFFS' EXHIBIT NO. 11 376 PLAINTIFFS' EXHIBIT NO. 12 388 19 PLAINTIFFS' EXHIBIT NO. 13 421 PLAINTIFFS' EXHIBIT NO. 14 458 20 21 22 23 24 Page 10 1 COMES RAY FULLER, CALLED BY THE 2 PLAINTIFF, AND AFTER FIRST BEING DULY SWORN, WAS 3 DEPOSED AND TESTIFIED AS FOLLOWS: 4 * * * * * * * * * * 5 MR. MYERS: So the record is clear, 6 this deposition, like yesterday, is being taken 7 in the same cases that yesterday's deposition was 8 taken in. It's been noticed in those cases, and 9 for purposes of the Huslig case in Kansas and 10 your Texas state court cases, as I understand it 11 we have agreed that the multi-district 12 confidentiality order shall govern the 13 deposition. Is that right? 14 MR. SMITH: Correct. 15 MR. HARRIS: We're agreeable to that, 16 as well. 17 * * * * * * * * * * 18 DIRECT EXAMINATION 19 BY MR. SMITH: 20 Q. Would you please state your 21 name, sir? 22 A. My name is Ray Fuller. 23 Q. Do you have a middle name, 24 Doctor Fuller? Page 11 1 A. Yes, I do. 2 Q. Can I have it, please? 3 A. It's Ward, W-A-R-D. 4 Q. How old a man are you, sir? 5 A. Let's see, I'm fifty-eight. 6 Q. And your residence address, 7 please? 8 A. XXXXXXXXXXXXXXXXXXXXXX 9 XXXXXXXXXXXXXXXXXXXXXXXXXXXXX. 10 Q. XXXXXXXXXXXXXXXXXXXXXXXXXX 11 XXXXXXXXXXXXXXXXXXXXX? 12 A. XXXXXXXXXXX. 13 Q. XXXXXXXXXXXXXXXX? 14 A. XXXXXXXXXXXXXXXXXX. 15 Q. XXXXXXXXXXXXXXXXXXXXXXXXXXXXX? 16 A. Yes. 17 Q. Does anybody live with you, 18 Doctor Fuller, at the XXXXXXXXXX address? 19 A. My wife and dog. 20 Q. Do you and your wife just have 21 one child? 22 A. No, we have two. 23 Q. Two. One is grown and not 24 living with you? Page 12 1 A. No, I'm sorry, I said my wife 2 and dog. My children, I'm sorry -- no, I have 3 two children, they don't live with me. 4 Q. Because they're grown? 5 A. Yes. 6 Q. How long have you lived at the 7 XXXXXXXXXXXXXXXX address? 8 A. About four years, I believe. 9 Q. And before the XXXXXXXXXX 10 address, where did you live? 11 A. XXXXXXXXXXXXXXXXXXXXXXXXX 12 XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX. 13 Q. How are you employed, sir? 14 A. I'm employed at Eli Lilly and 15 Company. 16 Q. And what is your present 17 position with Eli Lilly and Company? 18 A. My title is Lilly Research 19 Fellow. 20 MR. HARRIS: I'm sorry, what? 21 THE WITNESS: Lilly Research Fellow. 22 Q. Are you employed by the Eli 23 Lilly laboratories or Eli Lilly and Company, 24 Inc.? Page 13 1 A. I'm part of Lilly Research 2 Laboratories. 3 Q. Who currently is president of 4 Lilly Research Laboratories? 5 A. August Watanabe. 6 Q. August what? 7 A. Watanabe, W-A-T-A-N-A-B-E. 8 Q. And then under him are there 9 vice-presidents? 10 A. Yes. 11 Q. Do you report directly to one 12 of the vice-presidents, Doctor Fuller? 13 A. Yes, I do. 14 Q. Which vice-president do you 15 report to? 16 A. Stephen Paul. 17 Q. P-A-U-L? 18 A. Yes. 19 Q. And what is Stephen Paul's 20 position? 21 A. Vice-president of Lilly 22 Research Laboratories. 23 Q. Does he have a particular 24 division or a particular area of Page 14 1 responsibilities? 2 A. Yes. 3 Q. What is that, please, sir? 4 A. It's central nervous system, 5 gastrointestinal and genito-urinary research, or 6 something like that. 7 Q. Is Stephen Paul a medical 8 doctor? 9 A. Yes, he is. 10 Q. And do you know if Doctor Paul 11 has a specialty? 12 A. He's a psychiatrist. 13 Q. And you report directly to 14 Doctor Paul as a Lilly Research Fellow? 15 A. That's right. 16 Q. Is there any position known as 17 a senior research fellow? 18 A. No. 19 Q. What is the next position 20 below your position, do you follow what I'm 21 asking you? 22 A. Yes. Well, perhaps you should 23 explain what you're asking to be sure I 24 understand. Page 15 1 Q. I believe Doctor Wong is a 2 Lilly research advisor. 3 A. Yes. 4 Q. Or at least was at one time, 5 is that correct? 6 A. Yes. 7 Q. Would Doctor Wong's title of 8 Lilly research advisor be that title immediately 9 below yours? 10 A. Yes, that is correct. 11 Q. How many Lilly research 12 fellows are there in Lilly Research Labs? 13 A. I don't know the answer. 14 Q. Are there more than one Lilly 15 research fellows in the CNS division? 16 A. No. 17 Q. How many Lilly research 18 advisors are there currently in the CNS division, 19 such as Doctor Wong? 20 A. I'm not sure I know the 21 answer, maybe three. 22 Q. Who would be other Lilly 23 research advisors in addition to Doctor Wong in 24 the CNS division? Page 16 1 A. Jim Clements and David 2 Leander, and Dennis Zimmerman, which add up to 3 four. 4 Q. David Leander? 5 A. Yes. 6 Q. L-E-A-N-D-E-R? 7 A. That's correct. 8 Q. We know Doctor Wong is in CNS 9 research. 10 A. Yes. 11 Q. Is Doctor Clements in CNS 12 research? 13 A. Yes. 14 Q. Do you know whether or not -- 15 I assume Jim Clements is a Ph.D? 16 A. They all are Ph.Ds. 17 Q. Are any of them MDs? 18 A. No. 19 Q. Has Doctor Clements ever done 20 any work in connection with Fluoxetine? 21 A. Yes, he has. 22 Q. For how long has Doctor 23 Clements been involved in Fluoxetine research? 24 A. I don't know that I could give Page 17 1 you an accurate answer to that question. 2 Q. Is Doctor Clements a 3 biochemist? 4 A. No. 5 Q. What is his specialty? 6 A. His background is neuro 7 endocrinology. 8 Q. Doctor Leander, is he a 9 biochemist? 10 A. No. 11 Q. Has Doctor Leander done any 12 work in connection with Fluoxetine? 13 A. Yes, he has. 14 Q. What has he done? 15 A. He has done -- he is a 16 behavioral pharmacologist and has done behavior 17 related studies with it. 18 Q. And how long has Doctor 19 Leander been involved in behavioral studies in 20 connection with Fluoxetine Hydrochloride? 21 A. I think he began studies 22 before he joined Lilly. 23 Q. Where was he before he joined 24 Lilly? Page 18 1 A. University of North Carolina. 2 Q. Do you recall what he did in 3 connection with Fluoxetine prior to joining -- 4 A. I recall -- 5 Q. -- Lilly? 6 A. I recall some of the things he 7 did. 8 Q. Give me what you recall off 9 the top of your head. 10 A. They had to do with effects of 11 Fluoxetine alone or in combination with 12 5-hydroxytryptophan on food intake. 13 Q. Was he involved in any 14 clinical trials with respect to studying 15 Fluoxetine or Prozac in connection with treatment 16 of bulimia or weight control? 17 A. No, not to my knowledge. 18 Q. When did Doctor Leander join 19 Eli Lilly and Company? 20 A. I would say about in the early 21 1980s. 22 Q. But it's your understanding 23 that Doctor Leander did some work in connection 24 with Fluoxetine before he joined Lilly? Page 19 1 A. Yes. 2 Q. So it would have had to have 3 been done prior to the early '80s? 4 A. Yes. 5 Q. And he would have had to 6 secure Fluoxetine for his research that he was 7 doing in connection with food intake from Lilly, 8 would he not? 9 A. Yes. 10 Q. At that time Prozac had not 11 been approved as an antidepressant or for any 12 purposes in the early '80s, correct? 13 A. That's right. 14 Q. Do you recall the 15 circumstances in which he was able to do his 16 experiments and get Fluoxetine Hydrochloride from 17 Lilly? 18 A. I'm sure they were the same as 19 the circumstances by which other researchers 20 obtained it. 21 Q. Which would have been? 22 A. A request to Lilly with an 23 outline of the proposed studies and the assurance 24 that it would not be used in humans. Page 20 1 Q. All of Doctor Leander's 2 studies involved animals? 3 A. Yes. 4 Q. Doctor Zimmerman, has Doctor 5 Zimmerman done any work in connection with 6 Fluoxetine Hydrochloride? 7 A. Not so far as I know. 8 Q. What is Doctor Zimmerman's 9 specialty? 10 A. He's a medicinal chemist. 11 Q. Doctor Fuller, I was 12 introduced to you earlier, my name is Paul Smith, 13 and I represent several plaintiffs in claims 14 against Eli Lilly and Company by virtue of 15 circumstances surrounding the use of Fluoxetine 16 Hydrochloride, Prozac. Do you understand that? 17 A. Yes. 18 Q. I'm here to take your 19 deposition, and what we say here today is being 20 recorded and can be used as evidence in the trial 21 of any of these cases that Mister Myers was 22 describing earlier, correct, do you understand 23 that? 24 A. Yes. Page 21 1 Q. If I ask you any questions 2 that you don't understand, will you please let me 3 know? 4 A. Sure. 5 Q. We have various requirements 6 and restrictions imposed on us by various judges 7 throughout the country. One of those 8 restrictions that we're operating under is that 9 we, the plaintiffs, are somewhat limited in 10 securing proprietary information from Lilly 11 employees in connection with drugs other than 12 Prozac or Fluoxetine Hydrochloride, all right. I 13 would like to caution you now, and I'm sure 14 Mister Myers will help us out if we need any 15 help, if I ask you questions like, for instance, 16 I asked you Doctor Zimmerman worked on Fluoxetine 17 Hydrochloride and I said what area is he working 18 in, don't give me the names of any non-marketed 19 Eli Lilly compounds because we're not entitled to 20 that information, all right? 21 A. (Witness moves head up and 22 down.). 23 Q. Additionally, you're going to 24 need to give me an audible answer that can be Page 22 1 recorded rather than a shake of the head or 2 uh-huh or uh-uh. Would you do that for me, 3 please? 4 A. So the question to all right, 5 an answer would be yes. 6 MR. MYERS: You just need to make an 7 audible answer as opposed to a shake of the head 8 or an uh-huh or uh-uh because it's hard to 9 interpret that when it's typed up. 10 A. It's all right. 11 Q. How long have you been a Lilly 12 Research Fellow? 13 A. I believe since 1989. 14 Q. As a Lilly Research Fellow, 15 are you an officer of Lilly Research Labs? 16 A. No. 17 Q. Is the position Lilly Research 18 Fellow something that is given based on any 19 particular distinction? 20 A. What do you mean by 21 distinction? 22 Q. Number of years in service, 23 number of articles published, a particular 24 research milestone or something of that nature? Page 23 1 A. No, nothing in particular of 2 that nature. 3 Q. Who are the individuals who 4 are able at Lilly to confer the position of Lilly 5 Research Fellow on any particular scientist? 6 A. I think it would be Doctor 7 Watanabe and his staff. 8 Q. On a vice-presidential level, 9 I would assume? 10 A. I think that's correct. 11 Q. Has Doctor Watanabe been the 12 president of Lilly Research Labs ever since 13 you've been a Lilly Research Fellow? 14 A. No, he has only been president 15 for the last four months, I believe. 16 Q. Who was the president of Lilly 17 Research Labs prior to Doctor Watanabe? 18 A. Doctor Mel Perelman. 19 Q. It's my recollection that 20 Doctor Perelman is, by training, an internist? 21 A. No, that is not correct. 22 Q. What is his specialty? 23 A. He's a chemist. 24 Q. Doctor Perelman is not a Page 24 1 medical doctor? 2 A. That's correct. 3 Q. Was Doctor Perelman the 4 president of Lilly Research Labs when you became 5 a Lilly Research Fellow? 6 A. Yes, he was. 7 Q. And in what position was 8 Doctor Paul? 9 A. Doctor Paul was not a Lilly 10 employee, he was director of the National 11 Institute of Mental Health at that time, I 12 believe. 13 Q. When did Doctor Paul leave his 14 position as the director of the National 15 Institute of Mental Health to become the 16 vice-president of Lilly Research Labs? 17 A. It would have been less than 18 two years ago. 19 Q. Were you involved in the 20 decision to hire Doctor Paul from the National 21 Institute of Mental Health? 22 A. Maybe you should explain what 23 you mean by involved. 24 Q. Were you part of a committee Page 25 1 or group of individuals who assisted in the 2 selection of Doctor Paul as the new 3 vice-president in charge of the CNS division at 4 Lilly Research Labs? 5 A. I certainly talked with him 6 and that sort of thing. As far as being part of 7 the group that ultimately made the decision to 8 hire him, I would say no, I was not. 9 Q. Were you part of a search 10 committee or anything of that nature? 11 A. No, I was not. 12 Q. But you had known Doctor Paul 13 for some time prior to him coming with Lilly, had 14 you not? 15 A. Yes, uh-huh. 16 Q. How long have you known Doctor 17 Paul? 18 A. I don't remember exactly, 19 possibly ten or more years. 20 Q. How did you come to know 21 Doctor Paul? 22 A. I don't remember exactly how 23 we first met. We knew each other from scientific 24 meetings and that sort of thing. Page 26 1 Q. Was Doctor Paul with the 2 National Institute of Mental Health for the 3 entire time that you knew him up until the time 4 that he joined Lilly? 5 A. It's possible I met him before 6 he went to the National Institute of Mental 7 Health, but probably he was there at the time I 8 met him. 9 Q. Do you recall where Doctor 10 Paul was prior to him being with the National 11 Institute of Mental Health? 12 A. He was at the University of 13 Chicago at one time. I'm not sure if that was 14 immediately prior to NIMH. 15 Q. Do you have a staff of 16 individuals who work under you? 17 A. Yes, I do. 18 Q. And who are they? 19 A. There are two individuals, one 20 is Ken Perry and one is Susan Luecke, 21 L-U-E-C-K-E. 22 Q. And what do Mister Perry and 23 Ms. Luecke do? 24 A. They do laboratory experiments Page 27 1 in animals. 2 Q. What is their title, 3 laboratory assistants, laboratory technicians? 4 A. It's something like associate 5 biochemist. We have a system of titles that I 6 frankly don't remember the particular one for 7 them since I don't use it. 8 Q. And those systems and titles 9 change from time to time, don't they? 10 A. That's correct. 11 Q. Are you currently involved in 12 research? 13 A. Yes. 14 Q. Does your research currently 15 involve Fluoxetine Hydrochloride? 16 A. It does not principally 17 involve Fluoxetine Hydrochloride. We may, from 18 time to time, do animal experiments, we do from 19 time to time do animal experiments with 20 Fluoxetine. 21 Q. What was the last animal 22 experiment that you did employing Fluoxetine? 23 A. I don't know for sure that I 24 can remember the very last one. A recent one was Page 28 1 a series of experiments measuring extracellular 2 serotonin in rat brain after administration of 3 Fluoxetine. 4 Q. And were you studying 5 Fluoxetine and the effects of Fluoxetine in that 6 experiment? 7 A. Yes. 8 Q. And this was an experiment to 9 investigate another specific compound that was 10 under investigation by Lilly? 11 A. No, it was not. 12 Q. What were the results of that 13 experiment, Doctor Fuller? 14 A. Well, there were a series of 15 experiments, and they showed that Fluoxetine 16 increased the concentration of serotonin in 17 extracellular fluid in different regions of the 18 rat brain, and that it acted synergistically with 19 L-5-hydroxytryptophan, and that the increase was 20 dependent upon neurotransmitter release, and 21 particularly release from serotonin neurons. 22 Q. How long did that experiment 23 last, was it a series of experiments? 24 A. A series of experiments would Page 29 1 have lasted over a period of one to two years. 2 Q. This was not the first 3 experiment you had done in connection with 4 examining extracellular levels of serotonin in 5 rat brains, was it? 6 A. We began experiments like that 7 more than two years ago. 8 Q. You were doing experiments 9 investigating amounts of extracellular serotonin 10 in rat brains back in the '70's, were you not? 11 A. No, we were not. 12 Q. You were measuring quantities 13 or levels of serotonin in rat brains back in the 14 '70's, were you not? 15 A. Yes, that is right. 16 Q. What is new or distinct about 17 this latest project or experiment that you had 18 done? 19 A. The series of experiments that 20 I mentioned as having been done recently use the 21 technique of brain microdialysis, which was not 22 available back in the 1970's. 23 Q. Is that similar to kidney 24 dialysis? Page 30 1 A. It is similar only to the 2 extent that the type of microdialysis fiber used 3 is the same. 4 Q. Have you published the results 5 of that experiment yet? 6 A. We have published results from 7 those experiments, yes. 8 Q. When and where? 9 A. We published one paper in Life 10 Sciences and one paper in the Journal of Pharmacy 11 and Pharmacology, and those would have been 1992 12 and 1993, I think. 13 Q. So you're still active, Doctor 14 Fuller, I would assume, in research in connection 15 with Fluoxetine and serotonin and CNS compounds, 16 is that correct? 17 A. Yes, that's correct. 18 Q. As a Lilly Research Fellow, 19 are you free to pursue your research as you see 20 fit, within the bounds of reason, of course? 21 A. Yes. 22 Q. In other words, I guess what 23 I'm asking you is, Doctor Paul doesn't come to 24 you and say, Doctor Fuller, I want you to run a Page 31 1 particular experiment for me and I want you to 2 set it up in a particular manner? 3 A. That's correct, he does not. 4 Q. Your research ideas are your 5 ideas based on your knowledge, experience and 6 training, is that correct? 7 A. And things I learn from other 8 people, yes. 9 Q. Are you a member of any 10 particular project team at this time? 11 A. No. 12 Q. You were at one time the 13 Fluoxetine project team leader as I understand 14 it? 15 A. That is correct. 16 Q. When were you last a member of 17 the Fluoxetine project team? 18 A. Whenever it was disbanded, and 19 I don't remember what year that was. 20 Q. Give me an approximate date, 21 please. 22 A. It would have been, I suppose, 23 five years ago. 24 Q. Was it after Fluoxetine had Page 32 1 been approved -- 2 A. Yes. 3 Q. -- as Prozac for marketing to 4 human beings in the United States? 5 A. Yes, it was after that, I 6 believe. 7 Q. How long afterwards, shortly 8 afterwards? 9 A. Probably within two years 10 afterwards. 11 Q. We'll come back and talk about 12 this latest research that you've done later. 13 What I would like to do, Doctor Fuller, and I 14 don't want to take up too much time doing this, 15 but I would like to get a brief chronology of 16 your various activities within Eli Lilly and 17 Company, and I guess it might be just as easy to 18 work back. You've been a Lilly Research Fellow 19 since 1989, is that correct? 20 A. If I remember correctly, that 21 is. 22 Q. Prior to being a Lilly 23 Research Fellow, what was your position with Eli 24 Lilly and Company? Page 33 1 A. Research advisor. 2 Q. And can you give me the dates 3 that you held the title research advisor? 4 A. It would have been 1976 to 5 1989. 6 Q. During the time that you were 7 a research advisor with Lilly Research Labs, were 8 there any individuals in the CNS division who 9 were research fellows? 10 A. I don't think so. You're 11 traveling a thirteen-year period there, and to 12 the best of my recollection, no. 13 Q. Is Lilly Research Fellow a new 14 position that has been created within the last 15 eight or ten years? 16 A. I don't think it is. There 17 were -- I think it's the same title that existed 18 longer than that. 19 Q. Prior to your being named a 20 research fellow, were there any individuals in 21 the CNS division who had ever been research 22 fellows? 23 A. I don't remember for sure how 24 long the CNS division has existed as a CNS Page 34 1 division, I think the answer is no. 2 Q. When I say CNS division, I'm 3 talking about that group of scientists, 4 physicians and researchers who worked on drugs or 5 compounds that would be used in connection with 6 the brain or nervous system, whether it be called 7 CNS division or some other title. Do you follow 8 what I'm saying? 9 A. Yes, I do. 10 Q. During the period of time that 11 you were a research advisor with Lilly, did you 12 have an individual to whom you reported? 13 A. Yes, I did. 14 Q. And who was that? 15 A. Well, during that 16 thirteen-year period, it would have been 17 different people, I believe. One person was Doug 18 Morton. 19 Q. Doug Morton? 20 A. Yes. 21 Q. Who else? 22 A. Perhaps I reported to John 23 Whitney during that period. 24 Q. W-H-I-T-N-E-Y? Page 35 1 A. That's right. 2 Q. Anyone else, to whom you 3 reported during this -- 4 A. I think that may be all. 5 Q. What were their positions at 6 the time you reported to them? 7 A. I believe they, at the time, 8 were vice-presidents. 9 Q. Prior to becoming research 10 advisor in 1976, what was your job title? 11 A. It was research associate. 12 Q. And for what years did you 13 hold that title? 14 A. 1971 to 1975. 15 Q. During that period of time, 16 was there a research advisor to whom you 17 reported? 18 A. No. 19 Q. To whom did you report during 20 that period of time? 21 A. I reported to David Brennan. 22 Q. And what was his title? 23 A. Director of Biochemical and 24 Physiological Research, I think. Page 36 1 Q. And before you became a 2 research advisor with Lilly, what job title did 3 you hold? 4 MR. MYERS: You mean research 5 associate? 6 MR. SMITH: I'm sorry. 7 A. Head of the Department of 8 Metabolic Research. 9 Q. And how long did you hold that 10 position? 11 A. 1968 to 1971. 12 Q. And to whom did you report? 13 A. David Brennan. 14 Q. Was he at that time the 15 director of biochemical and psychological 16 research? 17 MR. MYERS: Physiological. 18 MR. SMITH: Physiological research. 19 A. That's right. 20 Q. Prior to being head of the 21 department of metabolic research, what was your 22 job title? 23 A. Research scientist. 24 Q. And to whom -- what period of Page 37 1 time did you -- 2 A. 1967 to 1968. 3 Q. And to whom did you report at 4 that time? 5 A. Irwin Slater. 6 Q. And before research scientist, 7 what was your position? 8 A. Senior pharmacologist. 9 Q. And for what years did you 10 hold that position? 11 A. 1963 to 1967. 12 Q. And to whom did you report at 13 that level? 14 A. Irwin Slater. 15 Q. Have you seen Doctor Slater 16 lately? 17 A. What do you mean by lately? 18 Q. This year. 19 A. No. 20 Q. He's still fine. 21 A. Good. 22 Q. I have seen him, he's fine. 23 A. Good, good. 24 MR. MYERS: Thank you for that report. Page 38 1 Q. Well, you're still friendly 2 with Doctor Slater, are you not? 3 A. Certainly. 4 Q. He holds you in the highest 5 regards. 6 A. The feeling is mutual. 7 Q. He doesn't hold me in any 8 regards, but -- 9 MR. HARRIS: We understand that, Paul. 10 Q. Before you were senior 11 pharmacologist, what was your position at Lilly? 12 A. I did not have one with Lilly. 13 Q. You started with Lilly in 14 1963? 15 A. That's right. 16 Q. Are you a pharmacologist, 17 Doctor Fuller? 18 A. Yes. 19 Q. And where did you get your 20 pharmacologist training? 21 A. My academic training was not 22 in pharmacology. 23 Q. All right. Does anybody -- 24 has anybody conferred upon you a degree as a Page 39 1 pharmacologist? 2 A. I have an honorary Doctor of 3 Science degree from the Purdue University School 4 of Pharmacy, so that probably qualifies as -- 5 Q. That's an honorary degree, 6 though, is it not? 7 A. That's right. 8 Q. And when they confer on an 9 individual an honorary doctor of whatever it is, 10 that means that that particular individual hadn't 11 gone through a formal curricula to secure that 12 particular honorary degree, is that correct? 13 A. No, that isn't what it means. 14 Q. Honorary doctor of a 15 particular area is not based on going to school 16 in a particular school of whatever discipline 17 that is, is it, it's by virtue of some 18 distinction that you attain by virtue of some 19 independent means, isn't that correct? 20 A. Distinction, accomplishments, 21 achievements, yes. 22 Q. But not necessarily the fact 23 that you went through that particular curriculum 24 in that particular school. Page 40 1 A. That's correct. 2 Q. Even though I believe you did 3 go to Purdue University, did you not? 4 A. Yes, I did. 5 Q. Before you joined Lilly in 6 1963, were you working on a full-time basis? 7 A. Yes, I was. 8 Q. Where? 9 A. At the Fort Wayne State 10 Hospital. 11 Q. In what capacity? 12 A. I was director of the research 13 laboratory. 14 Q. And for what years were you at 15 Fort Wayne State University? 16 A. 1961 to 1963. 17 Q. And prior to 1961, or 18 immediately before you went with Fort Wayne 19 State, you were a student, is that correct? 20 A. That is right. 21 Q. Tell us, then, Doctor Fuller, 22 the extent of your education starting with high 23 school. Where did you go to high school and when 24 did you graduate from high school? Page 41 1 A. Okay. I went to high school 2 at Anna Jonesborough Community High School in 3 Illinois. 4 MR. SMITH: Do you know where that is? 5 MS. ZETTLER: Uh-huh. 6 MR. SMITH: She's from Chicago. 7 MS. ZETTLER: The other end of the 8 state. 9 MS. ZETTLER: What town is that in? 10 THE WITNESS: It's in Anna. 11 Q. When did you graduate from 12 high school? 13 A. 1952. 14 Q. After high school? 15 A. Attended Southern Illinois 16 University. 17 Q. Did you graduate from Southern 18 Illinois University? 19 A. Yes. 20 Q. In what year? 21 A. Bachelor's degree in 1957. 22 Q. Bachelor of Science? 23 A. Bachelor of Arts, actually. 24 Q. What was your major in Page 42 1 college? 2 A. Chemistry. 3 Q. You majored in chemistry, but 4 the degree you received was a Bachelor of Arts? 5 A. That's correct. 6 Q. Why was that? 7 A. I was in the College of 8 Liberal Arts and Sciences, the Bachelor of Arts 9 degree meant that I had a foreign language 10 proficiency as well as a science degree or 11 training. 12 Q. Then I assume you did 13 postgraduate training after you were graduated 14 from Southern Illinois University? 15 A. Yes. 16 MS. ZETTLER: Do they still have 17 Halloween down there, a Halloween celebration? 18 THE WITNESS: We didn't do such 19 things. 20 MS. ZETTLER: Too bad. 21 Q. Where did you get your 22 postgraduate training? 23 A. I began it at Southern 24 Illinois University. Page 43 1 Q. In what discipline? 2 A. Microbiology. 3 Q. And did you complete a degree 4 at Southern Illinois University, postgraduate? 5 A. Yes. 6 Q. What degree did you receive 7 there? 8 A. Master of Arts. 9 Q. Were you taking some foreign 10 language in the graduate program also that would -- 11 A. I passed a proficiency exam. 12 Q. Then after -- when did you get 13 your Master's degree? 14 A. 1958. 15 Q. And then after you graduated 16 from Southern Illinois University, did you do 17 further training? 18 A. Yes. 19 Q. Where? 20 A. Purdue University. 21 Q. And you received a Ph.D from 22 Purdue? 23 A. That's right. 24 Q. In what year? Page 44 1 A. 1961. 2 Q. And in what discipline? 3 A. Biochemistry. 4 Q. Did you teach at Southern 5 Illinois University? 6 A. A little bit. 7 Q. Did you teach at Purdue? 8 A. A little bit. 9 Q. Were you employed part time 10 while you were either working on your Master's or 11 your Ph.D? 12 A. Yes. 13 Q. In what capacity? 14 A. As graduate research 15 assistant. 16 Q. Were you doing anything in 17 your work as a graduate research assistant 18 investigating central nervous system chemicals? 19 A. No. 20 Q. When you were at Fort Wayne 21 State Hospital, as I understand it you began and 22 ended as director of research at that 23 institution? 24 A. That's right. Page 45 1 Q. And what was the research that 2 you were participating in at that institution? 3 A. It was in general aimed at 4 understanding brain dysfunction. 5 Q. Can you be more specific? 6 A. Well, the objective of the 7 research program was to understand the 8 biochemical basis for brain dysfunction, 9 particularly mental retardation and psychiatric 10 illness. And the type of work that I did during 11 the two-year period there primarily involved 12 measuring -- doing analyses of body fluid samples 13 from mentally retarded subjects. 14 Q. Now when you say mentally 15 retarded subjects, you are drawing a distinction 16 from those individuals who have mental illnesses 17 and disorders? 18 A. That's correct. 19 Q. In other words, these are 20 individuals who, by virtue of some unfortunate 21 set of circumstances, did not have the 22 intelligence or were not able to develop to 23 attain that degree of intellect and functioning 24 that most of us who are normal attain, is that Page 46 1 right? 2 A. That's correct. 3 Q. As opposed to individuals who 4 have some particular psychiatric disorder, such 5 as schizophrenia, depressed individuals, or other 6 types of mental illnesses, is that correct? 7 A. That's correct. 8 Q. Was Fort Wayne State Hospital 9 an institution that housed and treated mentally 10 retarded and individuals who suffered from mental 11 disorders or illnesses? 12 A. Yes, but it was principally 13 mentally retarded. 14 Q. Do you recall at the time you 15 were there what the percentage of individuals who 16 were retarded versus mentally ill? 17 A. Well, there certainly was 18 overlap in that population, so I don't think one 19 can break down into percentages, at least I could 20 not do that. 21 Q. Did you publish any works in 22 connection with the research you did on the 23 biochemical basis of brain dysfunction? 24 A. Yes, we did. Page 47 1 Q. And was it more than one work? 2 A. Yes, it was. 3 Q. How many were there? 4 A. I believe there were three 5 papers all together. 6 Q. Did any of those papers have 7 to do with serotonin or the serotonin system? 8 A. No. 9 Q. Did any of those papers have 10 to do with neurotransmitters, specifically or 11 generally? 12 A. No. 13 Q. Was your work in connection 14 with that research in any way involved with 15 neurotransmission, in that fashion that your work 16 has been since at least 1975? 17 A. I would say the answer would 18 be no. 19 Q. What were the conclusions that 20 you drew from your research at Fort Wayne State 21 Hospital that you published in those three 22 papers? 23 A. Two of the papers had to do 24 with the finding of an increase in uric acid Page 48 1 concentration in the serum of patients with 2 Downs' Syndrome and the third had to do with a 3 chromosomal abnormality in the two siblings, 4 S-I-B-L-I-N-G-S. 5 Q. Did you conclude, based on 6 your research and your studies and your 7 experience at Fort Wayne State Hospital, that 8 mental dysfunction could have a biochemical basis 9 in individuals? 10 A. Well, that conclusion, I 11 think, was fairly obvious to those in the field 12 before I began doing research there. 13 Q. Was it generally recognized at 14 the time you were at Fort Wayne State Hospital 15 that some mental dysfunction could have a 16 biochemical basis? 17 A. I think so. 18 Q. And were you of the opinion at 19 that time that some mental dysfunction could have 20 a biochemical basis? 21 A. I'm not sure that I understand 22 what you're meaning by brain dysfunction could 23 have a biochemical basis as opposed to what other 24 kinds of basis. Page 49 1 Q. Maybe we need to define it 2 because I was using terms that -- I wrote down 3 terms that you had given me, and maybe you would 4 expand on that and describe for us in what manner 5 you're speaking of brain dysfunction and mental 6 dysfunction. 7 A. The brain, like other parts of 8 the body, is made up of molecules, and the 9 function of any part of the body involves 10 molecular changes so that when any part of the 11 body is dysfunctional, there would be some type 12 of molecular change that would be occurring, and 13 that would be as true for the brain as any other 14 part of the body, yes. 15 Q. Was it recognized then that 16 some, for use of a -- to use a broad term, that 17 some mental illnesses were caused or had a basis 18 in some biochemical factor? 19 A. So far as I know, those people 20 who were in the field realized that there would 21 be molecular abnormalities whenever there was a 22 functional abnormality, yes. 23 Q. You're familiar with the term 24 personality disorder? Page 50 1 A. Yes. 2 Q. Is that term used by mental 3 health care professionals? 4 A. Yes. 5 Q. And are there some personality 6 disorders that have a biochemical basis? 7 A. I think all personality 8 disorders would have a disordered molecular 9 processes going on. I don't think it's 10 meaningful to use the term some. 11 Q. You think all -- 12 A. Yes. 13 Q. -- personality disorders have 14 some biochemical basis that causes this disorder? 15 A. I don't think you can separate 16 thought and -- or mental function and molecular 17 changes as one causing the other, they must occur 18 together, I think. 19 Q. All right. Well -- 20 A. In other words, whenever I 21 think, there are molecular changes occurring, 22 whether I think about them or not. 23 Q. Do those molecular changes 24 cause you to think or is it because you think Page 51 1 that there are molecular changes? 2 A. There simply simultaneous 3 occurrences, one couldn't occur without the 4 other. 5 Q. Well, I don't think about my 6 heart beating, I don't have to consciously cause 7 a particular brain function to cause my heart to 8 beat, correct? 9 A. I would believe that, yes. 10 Q. Because you don't think to 11 cause your heart to beat either, do you, Doctor 12 Fuller? 13 A. That's correct. 14 Q. Our heart beat is controlled 15 by impulses from the brain or impulses that 16 originate from the brain, do they not? 17 A. It is influenced by that, 18 certainly. 19 Q. But we don't have to 20 consciously cause our heart to beat, do we? 21 A. That's right. 22 Q. Our heart will beat when we're 23 asleep, correct? 24 A. That's right. Page 52 1 Q. Our heart may beat faster as a 2 result of being afraid, mightent it? 3 A. Yes. 4 Q. But we don't control that 5 either, do we, that increase in heart rate by 6 virtue of our perception of fear? 7 A. It would be the perception of 8 fear that would lead to the physiological changes 9 that would cause the heart to beat faster, yes. 10 Q. But that's not something that 11 we think about, heart beat faster, I'm afraid, is 12 it? 13 A. I suspect that's true for most 14 people. 15 Q. That could be -- the same 16 could be said for respiration, correct? 17 A. Yes. 18 Q. Digestion? 19 A. Yes. 20 Q. A function of many of our 21 organ systems, we don't -- it's controlled by the 22 brain or impulses that control that originate 23 from the brain, but we don't have to consciously 24 think about that, correct? Page 53 1 A. That's correct. 2 Q. Now, from that, there are -- 3 can we move to functions of the brain that 4 dysfunction and result in physical illness, for 5 instance, are there diseases or anatomical 6 problems with the brain that can result in 7 physical illness? 8 A. Yes, I'm sure there are. 9 Q. Can you give me some of those, 10 an example of something that is a disorder of the 11 brain or nervous system that results in physical 12 illness? 13 A. Oh, I don't know that I can 14 think of a particular disease, if that's what 15 you're looking for. 16 Q. How about polio, doesn't that -- 17 isn't that a disease of the nervous system or an 18 abnormality of the nervous system that causes a 19 physical illness? 20 A. That -- you might say so, I 21 think, yes. 22 Q. Epilepsy, is that a disorder 23 of the brain or nervous system that causes a 24 physical illness? Page 54 1 A. I guess it depends on what you 2 mean by physical illness. 3 Q. Something that affects the 4 physiological function of the body that results 5 in an abnormal condition. 6 A. Such as convulsions in that 7 case? 8 Q. For instance, yes. 9 A. Sure. 10 Q. Now, are there brain 11 dysfunctions or biochemical bases for mental 12 illnesses? 13 A. Again, there are -- as Ralph 14 Gerard said, behind every crooked thought there 15 lies a crooked molecule. 16 Q. Who is Ralph Gerard? 17 A. He was a very prominant 18 neuroscientist. 19 Q. And he said beyond -- 20 A. Behind every crooked thought 21 there lies a crooked molecule. I think I'm 22 quoting him correctly, that was the thought. 23 Q. When Doctor Gerard made that 24 statement, behind every crooked thought lies a Page 55 1 crooked molecule, what did he mean by that as far 2 as you understood the point he was trying to 3 make? 4 A. I think it's the same point I 5 was making earlier, and that is that the process 6 of thought or emotions involve molecular changes, 7 and those are simply occurring together and they 8 can't be separated. 9 Q. So it's well recognized by 10 you, as well as other scientists knowledgable in 11 the field, that our thoughts and the molecular 12 changes in our brains are intertwined? 13 A. Yes. 14 Q. Either thoughts cause 15 molecular changes in our brain or molecular 16 changes in our brain causes thought, is that 17 right? 18 A. I'm not sure I understood what 19 you meant by that. Those two things go together, 20 yes. 21 Q. It's kind of a chicken in the 22 egg -- is it kind of a chicken and the egg type 23 situation, you don't know whether the molecular 24 changes are causing the thoughts or the thoughts Page 56 1 are causing the molecular changes, but they're so 2 intertwined it's impossible to draw a 3 distinction? 4 A. I'm not sure it's meaningful 5 to even think in terms of cause and effect, they 6 simply are occurring together. 7 Q. All right. Are you saying 8 that a particular molecular change can cause a 9 particular thought? 10 A. I believe that could occur, 11 yes. 12 Q. And is that generally accepted 13 scientifically? 14 A. I think so. 15 MR. MYERS: Can we take a short break? 16 MR. SMITH: Yes. 17 (A SHORT RECESS WAS TAKEN.) 18 Q. Is Doctor Gerard still alive? 19 A. No, he's not. 20 Q. And was he with a medical 21 school or? 22 A. Yes, I believe he was. 23 Q. Which school was he associated 24 with, do you recall? Page 57 1 A. I do not recall. 2 Q. Can you list for me, Doctor 3 Fuller, based on your experience and your 4 training and your research, some mental disorders 5 that have been established to be related to a 6 biochemical dysfunction in the brain? 7 A. Could you explain the question 8 a little bit more? 9 Q. Are there mental illnesses, as 10 those conditions have been described by 11 psychiatrists, schizophrenia, for example, are 12 there mental illnesses that have -- that have as 13 their basis a biochemical mental dysfunction? 14 A. Are you asking a single 15 biochemical change? 16 Q. Or a combination thereof. 17 A. I think most people believe 18 that schizophrenia, for example, is an example of 19 such a disease, that abnormality in dopamine 20 function may be one of the molecular changes that 21 is involved in schizophrenia. 22 Q. Any other mental illnesses? 23 A. I think depression is another 24 example of a mental illness where abnormalities Page 58 1 in the function of one or more transmitters is 2 thought by many to be involved. 3 Q. How about obsessive compulsive 4 disorders? 5 A. Again, I think in most such 6 disorders, many people believe there's some 7 abnormality. The identification of those 8 abnormalities and the understanding of them is 9 far from complete at this point. 10 Q. That's part of what you do as 11 a scientiest, is it not, Doctor Fuller, is to try 12 to get a greater understanding of the effect or 13 the relationship between mental dysfunctions and 14 some biochemical neurological change? 15 A. In a general sort of way, that 16 is correct. 17 Q. How about paranoia, does that -- 18 would that be a mental illness that has a 19 biochemical basis, at least in part? 20 A. I think that's often a 21 subgroup of schizophrenia. 22 Q. How about -- are you familiar 23 with the term sociopath? 24 A. I'm aware of the term, yes. Page 59 1 Q. Do you have any opinions 2 concerning whether or not those individuals who 3 were sociopaths have a biochemical disorder that 4 causes them to be sociopaths? 5 A. As I have explained, it's my 6 view that behavioral changes, behavior is 7 intimately associated with molecular changes. 8 Q. In the brain? 9 A. In the brain. So there could 10 not be one occurring without the other one, yes. 11 Q. Why did you leave Fort Wayne 12 State Hospital? 13 A. Because the facilities 14 available there to do research were not 15 satisfactory. 16 Q. When did you have as a goal in 17 mind research, when did you decide you wanted to 18 get into research as a profession? 19 A. It would have been late in my 20 undergraduate training. 21 Q. So I assume you looked at 22 various opportunities for further research at 23 some point in your career at Wayne State 24 Hospital? Page 60 1 A. Fort Wayne State Hospital, 2 yes, that is right. 3 Q. And did you apply for 4 positions in academia, academia -- did you apply 5 at any other universities? 6 A. Yes. 7 Q. What universities did you seek 8 positions at? 9 A. At that time, University of 10 Michigan. That may have been the only one. 11 Q. Did you apply for jobs in 12 private industries such as Lilly with any other -- 13 A. No, I didn't, not at that 14 time. 15 Q. Well, did you apply for jobs 16 with other companies after Lilly, after you 17 applied at Lilly? 18 A. I have not applied for any 19 positions at all since I have been at Lilly. 20 Q. I guess did you send -- my 21 question is, before you got the job with Lilly, 22 did you send resumes out to any other companies 23 other than Eli Lilly and Company? 24 A. I listed myself in the Page 61 1 placement service with the Federation of American 2 Societies for Experimental Biology and Medicine, 3 and to that extent my resume would have been 4 available to anyone who used that service. And 5 as far as did I specifically mail one directly to 6 any other company, I simply don't remember 7 thirty-one years ago. 8 Q. Do you recall if you 9 interviewed with any companies other than at Eli 10 Lilly? 11 A. I did not interview with any 12 other at that time. 13 Q. At the time you joined Lilly, 14 did you have any particular area of research that 15 you were interested in pursuing? 16 A. Yes. 17 Q. What was that? 18 A. It concerned monoamine oxidase 19 inhibitors and their effects on brain 20 neurotransmitters, including serotonin. 21 Q. Let me make sure I've got it 22 right. Your interest at the time you joined 23 Lilly was monoamine oxidase, MAOs? 24 A. My general interest was still Page 62 1 in what has continued to be in biochemical bases 2 of brain function and dysfunction. The specific 3 research that I joined Lilly to begin concerned 4 serotonin and other neurotransmitters, and one 5 particular project was the effects of monoamine 6 oxidase inhibitors on those neurotransmitters, 7 including serotonin. 8 Q. Can you define for us, please, 9 what a neurotransmitter is? 10 A. It's a substance that 11 transmits signals or messages from one nerve cell 12 to another. 13 Q. Could you analogize a 14 neurotransmitter to the wiring in an electrical 15 circuit transmitting energy from one source to 16 another, in a very crude basis? 17 A. I don't think that's a very 18 good analogy. 19 Q. Can you give me a little 20 better analogy or can you analogize it to 21 something else that would give me as a lay person 22 a little better idea of what a neurotransmitter 23 is, Doctor Fuller? 24 A. I can try to describe Page 63 1 neurotransmitters, I don't immediately think of 2 an analogy that would be helpful. 3 Q. All right. 4 A. But fundamentally, the process 5 of neurotransmission is one nerve cell or neuron 6 releasing a substance which has an influence on 7 an adjoining nerve cell, and that is the process 8 by which signals are transmitted from one neuron 9 to another. 10 Q. When you say signals, what do 11 you mean by signal? 12 A. I mean that this neuron 13 receives, in essence, a message or a signal. 14 When a molecule of a particular neurotransmitter 15 acts on it, then it does something, whatever it 16 has been preprogrammed to do in response to that 17 particular signal. 18 Q. Is all brain function the 19 result of neurotransmission? 20 A. Is all brain function -- I 21 don't know what you intend to include when you 22 say brain function. 23 Q. Is neurotransmission vital to 24 brain function? Page 64 1 A. Yes. 2 Q. Are neurotransmitters divided 3 or classified in any particular way? 4 A. They are by some people. 5 Q. All right. What is the 6 generally accepted classifications of 7 neurotransmitters? 8 A. Well, for example, people 9 often refer to monoamine neurotransmitters, and 10 by that, they would include serotonin, 11 norepinephrine, dopamine, epinephrine, and 12 possibly others. They might refer to 13 neuropeptide, neurotransmitters. 14 Q. That's a different class? 15 A. That would be a different 16 class. 17 Q. What are some of those? 18 A. Oh, substance P. 19 Q. Beg your pardon? 20 A. Substance P, capital P, 21 enkephalin, endorphin, neuropeptide Y, 22 cholecystokinin. 23 Q. Okay. We've got monoamine 24 neuropeptides. Any other general Page 65 1 classifications? 2 A. Well, there's different ways 3 you might group things so that there could be 4 other classifications inspected, I'm sure, but 5 those are a couple of common ones. 6 Q. Would all of the 7 neurotransmitters that we now know of fall into 8 either being a monoamine or a neuropeptide group? 9 A. No. For example acetylcholine 10 is a common neurotransmitter that would not fit 11 into either of those categories. Another general 12 category would be amino acid neurotransmitters, 13 and that would include things like gaba, lysin, 14 glutamate. 15 Q. What would be an example of 16 acetylcholine neurotransmitter? 17 A. Acetylcholine is a particular 18 neurotransmitter. It's not a neuropeptide, it's 19 not a monoamine, it's not an amino acid, so it 20 wouldn't fit into one of those groups. 21 Q. Any other of the major groups, 22 Doctor Fuller? 23 A. Those are probably the major 24 ones. Page 66 1 Q. And what is the reason for the 2 different grouping of those particular 3 neurotransmitters into those one, two, three, 4 four broad categories, is it based on their 5 chemical structure or based upon the derivation 6 of making those substances, how do you get that 7 classification? 8 A. Those categories are based on 9 chemical structures. 10 Q. Did you begin work at Lilly in 11 connection with the -- can I call them MAO, 12 because I can't pronounce monoamine. 13 A. MAOs is an enzyme, monamine 14 oxydase. So you certainly can use MAO to refer 15 to that enzyme. 16 Q. All right. Did you begin 17 working with MAOs at the time you began with 18 Lilly? 19 A. You may -- if you mean 20 monoamine oxidase inhibitors, where you could use 21 the plural, it would be MAOIs. 22 Q. Okay. 23 A. MAO just refers to one enzyme, 24 monoamine oxidase. Yes, I did. Page 67 1 Q. What was your first project 2 with Lilly, specifically? 3 A. It was to study a group of 4 MAOIs that had been synthesized by Jack Mills. 5 Q. Was serotonin involved in 6 that? 7 A. Yes. 8 Q. And would that have been in 9 1963 when you began? 10 A. It began March 11, 1963. 11 Q. Was that work done under 12 Doctor Slater's direction? 13 A. Yes. I assume you mean did I 14 report to Doctor Slater at the time I did the 15 work? 16 Q. Yes. 17 A. The answer is yes. 18 Q. Have you done any work on 19 serotonin, any experiments involving serotonin 20 prior to coming with Lilly in 1963? 21 A. No. 22 Q. Did that first work 23 specifically involve serotonin? 24 A. Yes. Page 68 1 Q. All right. And what 2 specifically was that that you did? 3 A. It was to measure the 4 influence of MAOIs on serotonin conservations in 5 the brain of laboratory animals. 6 Q. I thought that MAOs -- I 7 thought that serotonin was an MAO. 8 A. No, you're wrong. 9 Q. Okay. Help me then. 10 A. MAO refers to monoamine 11 oxydase, which is an enzyme, and it is an enzyme 12 that degrades monoamines. There are several 13 monoamines that are degraded by MAO, and one of 14 those monoamines is serotonin. So inhibitors of 15 MAO, which I have referred to as MAOIs, in 16 seeking to use your abbreviations, inhibitors of 17 MAO cause an increase in the brain concentrations 18 of the monoamines that would ordinarily have been 19 degraded by that enzyme, and therefore there is 20 an increased amount of serotonin, norepinephrine, 21 dopamine, epinephrine in the brain when one 22 inhibits MAOs. 23 Q. Well, would Fluoxetine be an 24 MAOI? Page 69 1 A. No. 2 Q. Why? 3 A. Why, it simply isn't an MAOI, 4 it does not inhibit monoamine oxydase. 5 Q. Fluoxetine inhibits serotonin 6 reuptake? 7 A. That's correct. 8 Q. When did you first begin work 9 using the Lilly compound that was later named 10 Fluoxetine? 11 A. 1972. 12 Q. I believe that compound was 13 Lilly one one -- do you remember? 14 A. The Hydrochloride salt, which 15 is probably what you're trying to remember the 16 number for, was number -- had the number one one 17 oh one four oh. 18 Q. One one oh one four oh. 19 A. Yes. 20 Q. And that was Fluoxetine 21 Hydrochloride? 22 A. That's correct. 23 Q. And what did you do first in 24 connection with one one oh one four oh Fluoxetine Page 70 1 Hydrochloride? 2 A. Well, let me explain that the 3 molecule Fluoxetine was first synthesized as an 4 oxalate salt, which has a different number, eight 5 two eight one six. So I assume you're asking me -- 6 you're not trying to make a distinction between 7 eight two eight one six and one one oh one four 8 oh. 9 Q. Right. 10 A. You're simply asking me what 11 did I do first in relation to this molecule. 12 Q. Yes. Was that in 1972 -- 13 A. Yes. 14 Q. -- that you first did any work 15 in connection with Fluoxetine? 16 A. Yes. 17 Q. Okay. 18 A. I measured its effects on 19 brain serotonin in rats and mice, and on 20 serotonin metabolism, and on the depletion of 21 serotonin by other drugs, and on the effects of 22 other drugs on other monoamines. 23 Q. Who had synthesized 24 Fluoxetine? Page 71 1 A. Brian Molloy's laboratory, I 2 think Brian Molloy with the assistance of Ken 3 Houser. 4 Q. And Brian Molloy, at that 5 time, was an employee of Eli Lilly and Company? 6 A. Yes, he was. 7 Q. Did you have anything to do 8 with the synthesis of Fluoxetine? 9 A. No, I did not. 10 Q. Did Doctor Wong have anything 11 to do with the synthesis of Fluoxetine? 12 A. No, he did not. 13 Q. But you and Doctor Wong did 14 some of the initial work that established 15 Fluoxetine as a serotonin reuptake inhibitor, 16 isn't that correct? 17 A. That is correct. 18 Q. And explain to me what that 19 work did, what was your role that makes you kind 20 of a co-founder or co-inventer or co-developer of 21 Fluoxetine? 22 A. When Doctor Wong first found 23 that Fluoxetine, as it was later called, 24 inhibited the uptake of radioactive serotonin by Page 72 1 rat brain synaptosomes in vitro, in the test 2 tube. We immediately began experiments to 3 determine whether that compound would inhibit 4 serotonin uptake selectively in animals, rats and 5 mice. 6 Q. So Doctor Wong's first work 7 was in vitro? 8 A. That's correct. 9 Q. Which is a scientific way of 10 saying he was doing it in the test tube and not 11 using living organisms. 12 A. That's correct. 13 Q. Doctor Wong's work was in the 14 test tube, and your work originally involved 15 applying that knowledge or research to living 16 animals? 17 A. The initial work that we both 18 did is as you described it, yes. 19 Q. Okay. Specifically what did 20 you do first? 21 A. The first experiments that we 22 did were to show that this compound prevented 23 serotonin depletion by par-Chloroamphetamine, 24 which was evidenced that it blocked the serotonin Page 73 1 uptake carrier in the rat brain in vitro, in the 2 mouse brain, and to show that it caused a 3 decrease in serotonin turnover as a result of 4 that block of serotonin uptake. Serotonin 5 turnover being measured by a decrease in the 6 brain concentration of the serotonin metabolyte, 7 5-hydroxyindoleacetic acid, and measured in other 8 ways as well, and it had these effects without 9 blocking the uptake of norepinephrine because it 10 did not antagonize norepinephrine depletion by 11 drugs that depleted norepinephrine through a 12 carrier-dependent mechanism. 13 Q. Did you do that by exposing 14 MAOIs to the chemical Fluoxetine? 15 A. We administered Fluoxetine 16 initially by ingestion, and in some experiments 17 by oral gavage. 18 Q. Okay. First you injected a 19 mouse with some Fluoxetine, is that correct? 20 A. We injected Fluoxetine into 21 mice, I believe is the correct way of saying it. 22 Q. I may not say some things in 23 the proper scientific way, so bear with me. It's 24 not my intent to confuse you. I'm probably just Page 74 1 confusing myself, Doctor Fuller. 2 You injected some Fluoxetine 3 into a mouse, how did you know how much 4 Fluoxetine to give to the mouse? 5 A. We gave various amounts to 6 determine what amount was effective in blocking 7 the serotonin uptake carrier. 8 Q. All right. What was the first 9 amount that you injected? 10 A. I could not remember the 11 precise doses in the first experiment, but in 12 general, the kind of doses that we gave to rats 13 and mice were between point one and ten milligram 14 per kilogram of body weight. 15 Q. How would that convert to an 16 amount of Fluoxetine being given to a human? 17 A. The typical dose of Fluoxetine 18 in humans is twenty milligram per day, which 19 would, in a sixty kilogram human, which would be 20 about an average weight individual, would 21 translate to about point three milligram per 22 kilogram. 23 Q. So were you giving less or 24 more? Page 75 1 A. We were giving a range on both 2 sides of the dose that is now used in humans. 3 Q. This wasn't, I assume, a toxic 4 dose -- 5 A. These were not toxic doses. 6 Q. -- to mice. 7 A. That's correct, these were not 8 toxic doses to mice. 9 Q. You did later, I assume, or 10 somebody at Lilly did some toxicity studies, is 11 that correct? 12 A. That is correct, other people 13 did. 14 Q. But this is -- what you were 15 doing was even earlier than the toxicity studies, 16 you were trying to see whether or not at 17 particular level you could demonstrate any effect 18 on the brain chemistry of a mouse? 19 A. That's correct. 20 Q. Before you gave the Fluoxetine 21 to a mouse, Doctor Wong had already demonstrated 22 that it would inhibit serotonin reuptake by using 23 just chemicals, is that right? 24 A. No, he used what are called Page 76 1 synaptosomes from rat brain. 2 Q. But those synaptosomes were 3 parts of rat brains that hadn't been exposed -- 4 A. That's correct. 5 Q. -- while they were alive to 6 Fluoxetine? 7 A. That's correct, initially 8 that's correct. 9 Q. And what you were doing was 10 exposing mice to Fluoxetine while they were 11 alive? 12 A. Mice and rats. 13 Q. And was this first experiment 14 that you did an experiment in any way to observe 15 the behavior of the rats or mice or was it simply 16 to expose the rats and mice to Fluoxetine to be 17 able to measure whether or not the chemical was 18 inhibiting the serotonin reuptake? 19 A. The primary purpose was the 20 latter. We certainly did observe the animals 21 after we treated them, however. 22 Q. Was there a specific protocol 23 or experiment outline that required that you 24 observe the mice? Page 77 1 MR. MYERS: Mice and rats. 2 A. I don't understand what you 3 mean by a protocol that required it. We did the 4 experiments all within my own laboratory, and we 5 designed the experiments, and the experiments 6 were to administer the drug, and then at some 7 specified time interval thereafter, kill the 8 animals and make a measurement in their brain. 9 And during the interval between the time we 10 injected the drug and the time we killed them, we 11 did observe them. 12 Q. Was there any written criteria 13 with respect to when you would observe those 14 rodents and what particular characteristics you 15 would observe in those initial experiments? 16 A. Not in any more detail than I 17 just gave you, I don't think. 18 Q. Were there any written records 19 of what you observed, did you keep notes and say, 20 you know, rats seem sleepy, rats seem agitated, 21 rats are not eating today, rats are engaging in 22 any particular behavior? 23 A. Yes, we always keep reports 24 from the experiments with any sort of -- with not Page 78 1 only with all the data that are measured, let's 2 say serotonin concentration, but anything that's 3 noticed about the rats' behavior. 4 Q. What would you have done with 5 those written reports? 6 A. There weren't any behavioral 7 observations with Fluoxetine, there weren't any 8 behavioral changes that were written down because 9 there weren't any. In other words, you couldn't 10 tell any difference in Fluoxetine treated rats 11 from the controlled group. 12 Q. Regardless initially of the 13 dosage that you -- 14 A. That's correct. 15 Q. -- administered. Did you -- 16 you subjected the rodents to varying doses of 17 Fluoxetine, correct? 18 A. Yes. 19 Q. Over the course of the 20 experiment. 21 A. Yes. 22 Q. And did you subject the 23 rodents to treatment with the Fluoxetine over 24 varying periods of time? Page 79 1 A. Yes. 2 Q. All right. What were the time 3 periods that you were employing? 4 A. We measured -- whatever 5 changes we observed, we measured a full-time 6 course on them to determine how long they would 7 last, and we would have used times anywhere 8 between probably thirty minutes after treatment 9 and forty-eight hours after treatment. 10 Q. So forty-eight hours was the 11 longest period that you kept the rodents alive 12 from the time of first administration up until 13 the time that you sacrificed the rat? 14 A. That may be true. Again, 15 picking that time from memory, but for the most 16 part, I can -- what I remember is how long the 17 effects lasted. For example, the decrease in 18 5-hydroxyindoleacetic acid was still present at 19 twenty-four hours, I believe, and was not present 20 at forty-eight hours. It's possible there was a 21 longer time than forty-eight hours that was 22 included in the measurement as well, but I 23 wouldn't remember that because the effect didn't 24 last that long. Page 80 1 Q. When you say the effect, you 2 mean the serotonin reuptake inhibition? 3 A. Well, the effect I referred to 4 was one particular consequence of that, the 5 decrease in 5-hydroxyindoleacetic acid. 6 Q. When you say the decrease in 7 5-hydroxyindoleacetic acid, whatever it was that 8 you said, are you talking about serotonin levels 9 being reduced? 10 A. No. 5-hydroxyindoleacetic acid 11 is a metabolite of serotonin. The levels of 12 5-hydroxyindoleacetic acid are reduced, levels of 13 serotonin are not reduced. 14 Q. So by virtue of the -- is this 15 called 5-HT? 16 A. Serotonin is commonly 17 abbreviated 5-HT, 5-hydroxyindoleacetic acid is 18 commonly abbreviated 5-HIAA. 19 Q. So your first study, you were 20 just measuring 5-HIAA, the metabolite? 21 A. No. In all those experiments, 22 we measured both -- with serotonin, 5-HT, there 23 is not a change in the amount of serotonin as a 24 result of uptake inhibition. There is a change Page 81 1 in the concentration of 5-HIAA, a decrease, and 2 that decrease, I was saying, persisted for 3 twenty-four hours, but not forty-eight hours 4 after the administration of Fluoxetine. 5 Q. Does that decrease in 5-HIAA 6 mean that the reuptake of serotonin is being 7 inhibited? 8 A. That, in conjunction with 9 other experimental data, means just that, yes. 10 Q. But there is no change, you 11 found no changes in your measurements of the 12 level of serotonin itself? 13 A. The concentration of serotonin 14 itself, the total tissue concentration, didn't 15 change, that's correct. 16 Q. Have you ever done any 17 experiment where the concentration did change, of 18 serotonin? 19 A. By and large, with serotonin 20 uptake inhibitors, the tissue of levels of 21 serotonin, total amount of serotonin tissue, 22 doesn't change. There may be a slight increase 23 at times, but typically there is essentially no 24 change. Page 82 1 Q. So the answer to my question 2 would be no, we have never done any studies to 3 determine that there was a change in serotonin 4 levels in the tissues? 5 MR. MYERS: Before he answers, let me 6 object to the form. You're saying he never did 7 the studies, that's not his testimony. He said 8 he did studies, and I think he said he didn't 9 observe a change. 10 Q. There were no studies that 11 demonstrated any change in serotonin levels, is 12 that correct? 13 A. We have measured serotonin 14 levels in the tissues of rats and mice in many, 15 many experiments with Fluoxetine over the years, 16 sometimes measuring in whole brain, sometimes 17 measuring in particular regions of the brain, 18 such as hypothalamus, hippocampus, striatum, 19 cortex, something else, measuring at different 20 times, as early as thirty minutes, as long as 21 forty-eight hours or more. In most of those 22 experiments, there was not a statistically 23 significant change in the amount of serotonin. 24 In some experiments, some brain regions at some Page 83 1 time, as I recall, there were small, but 2 statistically significant increases in the amount 3 of serotonin. That is not an effect that one 4 focuses on with serotonin uptake inhibitors in 5 general. 6 Q. Why is that, Doctor? 7 A. Because they don't cause 8 changes in the amount of serotonin. What they do 9 is block the serotonin uptake and increase its 10 function, but the total amount of serotonin in 11 the brain doesn't change as a result of that. So 12 that is not a useful indicator of their effects. 13 The useful indicator is 5-hydroxyindoleacetic 14 acid concentration. 15 Q. And, so, when that 16 concentration of 5-HIAA goes down, that means 17 you're having a greater inhibition of reuptake? 18 A. There could be other reasons 19 for that going down, but with a drug such as 20 Fluoxetine, where you show in other kinds of 21 experiments that it does not do any of the other 22 things that might have led to that decrease, then 23 the decrease is an indicator of the inhibition of 24 serotonin uptake. Page 84 1 Q. So my original statement is 2 basically correct or generally correct? 3 A. Which original statement? 4 Q. The one where if you have 5 generally levels of 5-HIAA going up, seeing 6 increased levels of 5-HIAA, that means that 7 you're having an increase in serotonin reuptake. 8 A. No. That was neither your 9 original statement nor is that a correct 10 statement. 11 Q. Okay. Help me then, Doctor 12 Fuller. And again, I'm not trying to play word 13 games with you and I'm not trying to prove any 14 particular point, I'm just trying to get some 15 knowledge of what appears to me to be an 16 extremely complex subject, which I'm sure to you 17 is like falling off a log because you've been 18 doing it -- because you're real smart, number 19 one, and number two, you've been doing it for a 20 long period of time. I don't fit in either 21 classification, so I need your help. 22 A. Let me restate it. When 23 serotonin uptake is inhibited, one consequence is 24 a decrease in serotonin turnover, one measure of Page 85 1 which is a decrease in 5-HIAA concentration. 2 Q. Is a decrease? 3 A. A decrease. So that with a 4 drug such as Fluoxetine, the decrease in 5-HIAA 5 is a measure of the dose response effect on 6 serotonin uptake, and it's a measure of the time 7 course of the effect of serotonin. In other 8 words, if 5-HIAA levels remain decreased for 9 twenty-four hours, that indicates the drug is 10 inhibiting serotonin uptake for that period of 11 time. 12 Q. And is that what you found? 13 A. Yes, it is. 14 Q. What was the significance of 15 this finding in connection with the purpose of 16 your research? 17 A. The significance of the 18 collective results of the experiments we did was 19 to show that serotonin -- that Fluoxetine was 20 effective in blocking serotonin uptake, in vitro, 21 in rats and mice. That it had an adequate 22 duration of action, and that it was selective in 23 not blocking the uptake of other monoamines. 24 Q. What is the importance of it Page 86 1 being selective in not blocking the uptake of 2 other neurotransmitters or is there any 3 importance? 4 A. Well, there can be importance 5 in various contexts. One scientifically 6 interesting and exciting aspect is that at the 7 time it was the first drug that had been 8 discovered which had this kind of selectivity. 9 Drugs were known which blocked serotonin uptake, 10 but they didn't do so selectively, they also 11 affected the uptake of other neurotransmitters. 12 Having a drug that selectively blocked serotonin 13 uptake, then provided a pharmacologic agent which 14 would only increase serotonin function, and that 15 was useful to a scientist interested in 16 understanding more about the physiological role 17 of serotonin, and it was important in terms of 18 the potential usefulness of this agent as a drug. 19 Q. And what was the -- what did 20 you, as one of the initial researchers on this 21 project, see as some of the uses that this drug 22 could have? 23 A. Well, in 1972 and early 1973, 24 which is the initial period of study that we are Page 87 1 talking about, it was commonly believed that 2 serotonin was an important neurotransmitter in 3 depression, and that the action of the 4 antidepressant drugs which were available at that 5 time probably importantly involved serotonin. So 6 clearly, the potential use as an antidepressant 7 drug was apparent. And in addition, serotonin 8 had been postulated to be possibly important in 9 some other psychiatric diseases such as 10 schizophrenia and obsessive compulsive disorder. 11 And it was also believed that enhancing serotonin 12 function would reduce appetite and be a useful 13 treatment for obesity, and those are some of the 14 therapeutic applications that we considered. 15 Q. HT been demonstrated prior to 16 1972 and 1973 that Fluoxetine -- that serotonin, 17 as a neurotransmitter, had effect on appetite or 18 was that something that you found, Doctor Fuller? 19 A. It had -- there was evidence 20 that serotonin affected appetite, yes. 21 Q. Do you recall what the nature 22 of that evidence was? 23 A. Well, for example, one piece 24 of evidence was that there was a drug which was, Page 88 1 I believe, already marketed at that time, called 2 fenfluramine, which was thought to act by 3 increasing serotonin function. 4 Q. And had an effect on appetite? 5 A. Yes. 6 Q. All right. Was there any 7 evidence in existence at that time that serotonin 8 would or could have an effect on -- or serotonin 9 level could be implicated in schizophrenia or 10 obsessive compulsive disorders? 11 A. Yes. For example, Richard 12 Wyatt and colleagues at the National Institute of 13 Mental Health were publishing papers at that time 14 based on the administration of the serotonin 15 precursor, L-5-hydroxytryptophan. 16 Q. When you say precursor, 17 explain to us what you mean by that? 18 A. L-5-hydroxytryptophan is the 19 immediate precursor before serotonin, that is 20 L-5-hydroxytryptophan is converted to serotonin 21 in the body, it is part of the pathway by which 22 the body makes serotonin. And 23 L-5-hydroxytryptophan is an amino acid which can 24 be given and that will cross the blood brain Page 89 1 barrier and be converted to serotonin in the 2 brain. And Dick Wyatt and his collegues were 3 giving 5-hydroxytryptophan to chronic 4 schizophrenic patients and reporting beneficial, 5 theraputic benefit, and interpreting the 6 enhancement of serotonin function could be useful 7 in treating schizophrenia. 8 Q. Has that been proven to be the 9 case? 10 A. No, I don't think it has. 11 Q. Has it been proven to not be 12 the case? 13 A. I don't know that it has been 14 proven to not be the case, but I think most 15 people no longer believe that is a promising 16 approach to schizophrenia. 17 Q. And as I understand it, 18 research is still ongoing in connection with 19 obsessive compulsive disorders and the appetite 20 suppressant qualities of the serotonin system? 21 A. That's correct. 22 Q. And in fact Fluoxetine is 23 being investigated for those purposes? 24 A. There are several publications Page 90 1 and studies that have been done with Fluoxetine 2 for those purposes. 3 Q. Do you have an opinion in 4 connection with respect to whether or not 5 Fluoxetine will be useful as an appetite 6 suppressant? 7 A. There are clearly published 8 studies that suggest it is useful, yes. 9 Q. Have you done any studies in 10 that connection? 11 A. What I'm referring to here are 12 studies in humans, and no, I have not done any 13 studies on humans. 14 Q. Do you have an opinion 15 concerning whether or not Fluoxetine can be 16 useful as a therapy for appetite control? 17 A. Yes, based on those published 18 studies that I just referred to. 19 Q. And what is that opinion? 20 A. It appears to be useful. 21 Q. And do you have an opinion 22 concerning whether or not Fluoxetine is going to 23 be useful in treatment of obsessive compulsive 24 disorders? Page 91 1 A. Based on the studies that I 2 just referred to, the clinical studies, I would 3 assume it is useful. 4 Q. And these are clinical studies 5 that have been done by Eli Lilly and Company, and 6 others? 7 A. These are clinical studies 8 that have been done by others, in some cases the 9 studies were sponsored by Eli Lilly and Company. 10 Q. Well, Lilly has underway 11 clinical trials where they're studying the use of 12 Fluoxetine in humans in connection with appetite 13 control and obsessive compulsive disorders, do 14 they not? 15 A. Lilly has certainly sponsored 16 such studies in the past. If you're asking are 17 there any ongoing, as of this day, I would not be 18 in a position to know that. 19 Q. All right. How about bulimia, 20 is Fluoxetine useful in treatment of the disorder 21 known as bulimia? 22 A. I believe it's approved for 23 that purpose in some countries, so the answer 24 would apparently be yes. Page 92 1 Q. What is it about Fluoxetine 2 that causes the inhibition of the reuptake of 3 serotonin? 4 A. It interacts directly with the 5 serotonin transporter. I'm not sure if there's 6 something you're asking beyond that or not. 7 Q. How does it act together with 8 the serotonin transporter? 9 A. It occupies the position on 10 the serotonin transporter where serotonin would 11 normally occupy it to be transported, and 12 therefore the serotonin can't be transported. 13 Q. When you say transporter, do 14 you mean receptor site? 15 A. No. The term receptor, as I 16 have used it, and is used conventionly in 17 neuropharmacology, refers to a site on the neuro 18 membrane which elicits some particular response 19 in the neuron. The term transporter is a 20 different type of macromolecule, the function 21 being to actually transport something from one 22 side of the cell membrane to the other side. So 23 a transporter and a receptor are different 24 entities. Page 93 1 Q. What is the transporter of 2 serotonin? 3 A. What is it? 4 Q. Yes. 5 A. It is a protein macromolecule 6 that exists on the serotonin nerve membrane. 7 Q. What is it called? 8 A. It's called the serotonin 9 transporter on the serotonin uptake carrier. 10 Q. I'm having a little difficulty 11 completely understanding this, and Doctor Wong 12 drew for us a diagram yesterday that helped us, I 13 thought, at the time, describing the neurons in 14 connection with the serotonin system in a nerve 15 in a brain, and how the serotonin moved past the 16 synaptic cleft and into the next -- moved from 17 the presynaptic neuron to the postsynaptic 18 neuron. Can you give us a visual demonstration 19 of that? 20 A. Well, I could draw a diagram 21 similar to what I've published in a number of my 22 publications. 23 Q. Would you do that for us? 24 A. I'm sure you've seen that. If Page 94 1 that would be helpful, I can try to reconstruct 2 it. 3 Q. Please. And again, we're 4 looking for some kind of understanding of this 5 subject that -- 6 A. These are the events that go 7 on at the -- I'm not an artist, please 8 understand. But I'm drawing a diagram to 9 illustrate the kind of events that go on at a 10 serotonin synapse, and in this diagram, this 11 structure is intended to represent a serotonin 12 nerve terminal that is making synaptic contact 13 with some sort of target neuron over here. And 14 the whole purpose of this connection is that this 15 neuron can send a signal to this neuron by means 16 of the molecule serotonin. And I typically draw 17 this by using the abbreviation 5-HT to indicate 18 serotonin. 5-HT is the chemical -- is the 19 abbreviation for the chemical name for serotonin, 20 which is 5-hydroxytryptamine. And that serotonin 21 is synthesized within the nerve. 22 Q. When you say synthesized 23 within the nerve, you mean serotonin is actually 24 manufactured there in the nerve? Page 95 1 A. That's correct. 2 Q. Okay. Is that where the 3 precursor comes in? 4 A. Exactly. The precursor that I 5 mentioned before is 5-hydroxytryptophan, which is 6 usually abbreviated five HTP. And it is formed 7 from the amino acid tryptophan, which I will just 8 call TRY. And the serotonin that is formed here -- 9 Q. Is that the purpose of this 10 neuron, the serotonin neuron, to manufacture and 11 then transport serotonin? 12 A. It certainly is one of its 13 purposes. 14 Q. Is its function for additional 15 purposes? 16 A. That's probably its major 17 purpose. I say that because an individual neuron 18 might be manufacturing more than one 19 neurotransmitter, for example. 20 Q. All right. 21 A. The serotonin is taken into 22 storage granules or vesicles, which I will just 23 illustrate with a little circle around it. And 24 these, then, are where the serotonin is actually Page 96 1 released from, at nerve impulse, out into this 2 synaptic space or synaptic gap. 3 Q. Or cleft? 4 A. Or cleft, right. Now there 5 are some serotonin neurons that probably aren't 6 making a tight synaptic contact with a 7 postsynaptic cell, but just have a variety of 8 neurons around it. But I'm just illustrating the 9 events that go on rather than -- this is not 10 intended to be anatomically correct in all cases. 11 And, so, there would be some serotonin out here 12 in this extracellular space, the synaptic cleft, 13 where there is a tight synaptic junction. 14 And on this neuron there would 15 be a receptor of some sort, which would be 16 sensitive to serotonin, in other words serotonin 17 would uniquely interact with this particular part 18 of a molecule so that this molecule would know 19 that it had been -- it had received a signal from 20 serotonin. 21 Q. Okay. 22 A. And it would do something then 23 in response to that. It could be -- it would be 24 whatever this neuron had been preprogrammed to do Page 97 1 in response to that, it might be to speed up or 2 slow down or do something differently. And then 3 the serotonin is inactivated by being taken out 4 of this synaptic cleft through the action of the 5 type of molecule that I have referred to as a 6 transporter or an uptake carrier, which I often 7 draw something like this to indicate sort of 8 something that's taking serotonin from out here 9 and putting it back in here. 10 Q. Is that molecule located on 11 the end of the neuron, that uptake? 12 A. It's probably located -- it's 13 located on the outer membrane of the neuron, 14 probably various places around it. And once the 15 serotonin is back inside, then it's already out 16 of contact with this receptor. 17 Q. So it doesn't act as a 18 neurotransmitter -- the neurotransmission must 19 occur in the synaptic cleft, is that what you're 20 saying? 21 A. Must occur outside the neuron, 22 as I just said. It may occur in a tight synaptic 23 cleft or there could be just another system, 24 another place in the brain where there isn't this Page 98 1 tight synaptic cleft, but rather there's other 2 neurons around out here somewhere that the 3 serotonin neuron reaches. 4 Q. Okay, well we'll -- 5 A. But in general, what you say 6 is correct. 7 Q. All right. 8 A. And the serotonin that is back 9 inside the neuron, then, can either be reused or 10 it can get destroyed by this enzyme that we 11 talked about earlier called monoamine oxydase. 12 And the product, major product, of that action is 13 what we have referred to before as 5-HIAA, 14 5-hydroxyindoleacetic acid. 15 Q. So when we see -- or when we 16 measure 5-HIAA, as you did in your experiments, 17 initially -- 18 A. Yes. 19 Q. -- you were measuring how much 20 serotonin was actually being converted to -- 21 would waste be the proper term or another -- 22 A. Converted to -- 23 Q. -- inactive chemical as a 24 neurotransmitter? Page 99 1 A. Converted to 5-HIAA is what 2 was happening. 3 Q. 5-HIAA is not a 4 neurotransmitter. 5 A. That's correct. 6 Q. Once serotonin becomes 5-HIAA, 7 it no longer is useful as a neurotransmitter? 8 A. So far as we know, that is 9 correct. 10 Q. And what does the body do with 11 5-HIAA? 12 A. It ends up excreting it in the 13 urine. 14 Q. So 5-HIAA is a waste product 15 of this neurotransmission system that we have in 16 our brains? And when I say waste product, I 17 don't mean it in some garbage dump, I mean it's 18 just the product that's no longer useful to the 19 human body in neurotransmission. 20 A. It is a product that is no 21 longer useful to the human body in 22 neurotransmission, so far as we know. 23 Q. Go ahead, I'm sorry, I didn't 24 mean to interrupt you. Page 100 1 A. That, essentially, is some of 2 the major events that go on. Obviously there are 3 lots of other things that go on in any cell in 4 the body, but these are some of the key events 5 that are unique to a serotonin neuron. 6 Q. You have depicted two neurons, 7 is that right? 8 A. Yes. 9 Q. Is one neuron called the 10 presynaptic neuron and another neuron called the 11 postsynaptic neuron? 12 A. When you're talking about a 13 particular synaptic junction, this one would be 14 called the presynaptic neuron, and this would be 15 called the postsynaptic neuron. 16 Q. Well, this postsynaptic neuron 17 doesn't manufacture and store serotonin, does it, 18 or does it? 19 A. There's no law that says it 20 could not also be a serotonin containing neuron, 21 but it would not necessarily be a serotonin 22 containing neuron. 23 Q. But in the process of 24 neurotransmission, the postsynaptic neuron Page 101 1 doesn't act as a manufacturer and storer of 2 serotonin, is that correct? 3 A. As I just said, the 4 postsynaptic neuron could be another serotonin 5 neuron or it might be a neuron that made some 6 other neurotransmitter. 7 Q. Could we in fact have a line 8 where this postsynaptic neuron in the chain of 9 things is just like the presynaptic neuron, it 10 also is performing the function of manufacture 11 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 14 context for this. 15 Q. Do you want to draw? 16 A. No, I don't want to draw 17 another picture. In the brain, each neuron is 18 sending signals to many other different neurons 19 and is receiving signals from many different 20 neurons. What we are looking at here is just one 21 synaptic contact between one neuron and another. 22 This same neuron may be sending signals to fifty 23 other neurons or a hundred or something like 24 that. Page 102 1 Q. Would those other signals be 2 other neurotransmitters like dopamine, 3 epinephrine and things of that nature? 4 A. Let's suppose this particular -- 5 let's suppose we were talking about one 6 particular serotonin neuron. And let's suppose 7 that this particular neuron was actually sending 8 signals to eighty-seven different neurons. I 9 just picked the number obviously out of the blue. 10 Could any one of those eighty-seven be another 11 serotonin neuron, sure it could. The chances are 12 that most of them, however, are neurons that use 13 other -- a variety of other neurotransmitters. 14 Q. All right. 15 A. I think that's what you were 16 asking. 17 Q. Okay. Can this pre- and 18 postsynaptic neuron be seen on a microscope? 19 A. Yes. Can a synaptic -- you're 20 asking can a synaptic junction be seen 21 microscopically? 22 Q. Yes. 23 A. Yes. 24 Q. What is the distance -- to get Page 103 1 some concept of what we're talking about, can you 2 give me the distance between -- within this 3 synaptic cleft? 4 A. It would be measured in 5 micrometers, it's a very, very small distance. 6 Q. The amount of serotonin that 7 is in the synaptic cleft in any particular time, 8 did I understand you to say that the volume of 9 that has never been measured? 10 A. I don't recall that I said 11 that. 12 Q. All right. Well, has the 13 volume of that substance at a particular synaptic 14 cleft ever been measured? 15 A. Within one individual synaptic 16 cleft? 17 Q. Yes, sir. 18 A. No, not to my knowledge. 19 Q. Would that be something that 20 could be done scientifically? 21 A. No, not to my knowledge at the 22 present time. 23 Q. We just don't have the 24 technology to do that? Page 104 1 A. That's correct. 2 Q. Would it be of any scientific 3 significance or importance, the volume or amount 4 of serotonin that exists within this synaptic 5 cleft? 6 A. The amount of serotonin that 7 exists is certainly of interest. 8 Q. Why is that, Doctor Fuller? 9 A. Well, this is -- it's because 10 what is important in the process of 11 neurotransmission is not how much serotonin is 12 sitting here in the vesicle. 13 Q. That's where it's stored? 14 A. Where it's stored. But rather 15 how much is actually transmitting a signal. 16 Q. Why is that important? 17 A. Why is that? 18 Q. Let me say it this way: How 19 does the amount of volume affect the quality or 20 quantity of the signal? 21 A. You're using the term volume, 22 I think, in a way that isn't conventionally used. 23 Volume ordinarily means the size of something or 24 how much space it occupies. The number of Page 105 1 serotonin molecules, for example, or the 2 concentration of serotonin here in the synaptic 3 cleft, I think is what you mean, is what 4 determines how much transmission is occurring via 5 this particular synapse. 6 Q. Why does that particular 7 concentration affect how much transmission is 8 going on, why is it that there are more -- the 9 higher the concentration, the more transmission 10 you're going to get? 11 A. Well, the higher the 12 concentration out here, the more this receptor is 13 going to be activated. 14 Q. What is the receptor doing 15 actually? 16 A. It's transmitting -- 17 transducing a signal. Whenever it is acted upon 18 by a serotonin molecule, it triggers some event 19 within this neuron which causes that neuron to do 20 something differently. 21 Q. Is it actually moving a 22 serotonin molecule from the synaptic cleft into 23 the receptor site into the postsynaptic neuron? 24 A. No. So far as we know, the Page 106 1 serotonin molecule only acts on the surface of 2 this receptor, and it causes that receptor to 3 change in conformation or some way which then 4 leads to some molecular changes inside the 5 neuron. 6 Q. Okay. So I understand, you're 7 actually not having a serotonin molecule move 8 physically from the presynaptic cleft to the 9 synaptic cleft into the postsynaptic neuron? 10 A. That's correct, that's why I 11 didn't draw any arrows -- 12 Q. Serotonin isn't moving across 13 from one neuron to another neuron, is that what 14 you're saying? 15 A. No, that's not what I'm 16 saying. 17 Q. Okay. 18 A. And that is not what you said. 19 What you said, and I agree with, is that 20 serotonin does not move into that neuron, it 21 indeed moves from this storage site into the 22 synaptic cleft, and then is removed primarily by 23 being transported back inside. So as far as we 24 know, it does not enter that neuron. Page 107 1 Q. So the effect that is 2 important is the effect on the postsynaptic 3 neuron's receptor site, is that correct? 4 A. That effect is important. 5 Q. Because that is 6 neurotransmission, isn't it, Doctor Fuller? 7 A. That's correct. 8 Q. The activation of serotonin on 9 the receptor site is neurotransmission? 10 A. In regard to this synapse, 11 right. 12 Q. Yes. 13 A. In general, the 14 neurotransmission is the action of a transmitter 15 on some receptor site to cause the target neuron 16 to do something. 17 Q. Now, what kinds of messages 18 does serotonin transport to the receptor site? 19 A. Well, it -- in terms 20 typically, a message of this sort is translated 21 through some second messenger pathway, and common 22 second messengers would include cyclic AMP, and a 23 neurotransmitter, when acting on a receptor, 24 might cause an increase or a decrease in the Page 108 1 amount of cyclic AMP inside this neuron. 2 Q. What is cyclic AMP? 3 A. It is a cyclic neucleotide 4 made up of adenosine, ribose and phosphate, and 5 it's simply one of the body's common, so-called, 6 second messengers. 7 Q. But what does it do? 8 A. It causes some event to take 9 place in the cells. 10 Q. It causes a molecular change -- 11 MR. HARRIS: Objection. Let him 12 finish the answer, Paul. 13 MR. MYERS: Yes. Were you through, 14 Ray? 15 THE WITNESS: Sure. 16 MR. SMITH: I apologize. 17 A. I had intended to say more, 18 but I said enough. 19 Q. Go ahead and -- 20 MR. HARRIS: Would you like to 21 apologize to me, Nancy? 22 MS. ZETTLER: No. 23 Q. We're trying to take your 24 deposition, but we're also trying to learn from Page 109 1 you and you're trying to explain to us, and I 2 appreciate that, and don't let me cut you off. 3 A. The changes in cyclic AMP 4 cause further molecular changes then. They -- it 5 might -- could lead to a conversion of an active 6 enzyme into an inactive form or vice versa. The 7 point is, it is called a second messenger because 8 it changes in response to a receptor activation, 9 and then it leads to further changes of some 10 sort. 11 Q. How does that 12 neurotransmission of serotonin at the receptor 13 site affect the way we think or feel or the way 14 we react? 15 A. Well, we are thinking and 16 feeling and reacting because of a very complex 17 series of molecular changes of this exact sort, 18 that are going on within our brains, and it is 19 the composite of those which causes us to have 20 particular changes or feelings or thoughts. If I 21 have a different thought now than I had a few 22 minutes ago, it is because there's a different 23 summation of neurotransmission that's going on. 24 Q. So if these receptor sites are Page 110 1 being utilized in different ways or responding in 2 different ways -- 3 A. Yes. 4 Q. -- our thoughts can be 5 affected, as our appetite or as other physical 6 and emotional feelings. Do you follow what I'm 7 saying? 8 A. I'm sorry, I didn't 9 understand. 10 Q. As I understand it, 11 neurotransmission occurs at the receptor site, 12 correct? 13 A. It begins at the receptor 14 site. 15 Q. But as far as this 16 illustration you've drawn us, the transfer -- 17 A. Uh-huh, the transfer -- 18 Q. -- must occur at the receptor 19 site? 20 A. Yes. 21 Q. So that's where 22 neurotransmission occurs, that's where the effect 23 of all this process is? 24 A. Okay. Page 111 1 Q. Is that correct, 2 scientifically? 3 A. That's correct as long as 4 you're sort of defining neurotransmission that 5 far. You could also think of neurotransmission 6 in a more global sense, but go ahead. 7 Q. But it doesn't make any 8 difference what is occurring presynaptically or -- 9 in the presynaptic neuron or postsynaptic neuron, 10 if the receptor sites are not receiving these 11 messages, then you're not going to have 12 neurotransmission or your neurotransmission will 13 be affected in some manner? 14 MR. MYERS: Let me object to the form 15 because I don't think he said it doesn't matter 16 what happens before or after. There's been no 17 such -- 18 Q. And I don't mean to imply 19 that. Because I believe that the entire basis of 20 your research and what you found is that if you 21 can increase the concentration of serotonin in 22 the synaptic cleft, you can affect the ability of 23 the receptor site to pass on the serotonin 24 message, is that right? Page 112 1 A. That is part of my research. 2 My research is much broader than that, in 3 general. 4 Q. I understand that, but that's 5 supposedly the beneficial effect of Fluoxetine? 6 A. So far as we know, the action 7 of Fluoxetine is to inhibit that transporter and 8 cause an increased number of serotonin molecules 9 to be in the synaptic cleft. 10 Q. And the increase in the amount 11 of serotonin molecules in the synaptic cleft 12 affects the receptor site? 13 A. Yes. 14 MR. SMITH: Why don't we go eat. 15 (A SHORT LUNCH RECESS WAS TAKEN.) 16 Q. (BY MR. SMITH) Doctor Fuller, 17 in connection with this, the drawing you've made, 18 you have drawn a synaptic cleft in between the 19 two neurons, is that correct? 20 A. Yes. 21 Q. Now, what holds the serotonin 22 within the synaptic cleft? The reason I ask that 23 is there's a space obviously on the top, and 24 there's a space on the bottom, and I understand Page 113 1 that you're not drawing this according to any 2 perfect anatomy, but can you give us an 3 explanation as to how the serotonin stays within 4 the synaptic cleft? 5 A. Well, there are no forces that 6 hold it within synaptic cleft. Every molecule of 7 serotonin that enters the synaptic cleft could 8 leave by prediffusion, for example. The evidence 9 is that the bulk of it, however, is actively 10 transported by the uptake carrier before it has 11 time to diffuse away. 12 Q. So there is, indeed, spaces 13 within the synaptic cleft that a certain number 14 of serotonin molecules can escape out of? 15 A. There is no physical barrier 16 to it escaping. 17 Q. Have there been any studies or 18 any experiments done to determine the percentage 19 of serotonin within the synaptic cleft that is 20 transported or taken back into the presynaptic 21 neuron versus that amount that could diffuse out 22 of that area? 23 A. No, not to my knowledge. 24 Q. Would that be something that Page 114 1 would be of scientific interest? 2 A. Yes, it would. 3 Q. Would it be of something that 4 would be of scientific value in 5 neuropharmacology? 6 A. You apparently are using the 7 word value to mean something different that 8 interest. Could you explain the differentiation 9 you're making? 10 Q. Could it have therapeutic or -- 11 could it have therapeutic ramifications with 12 respect to mental conditions or illnesses? 13 A. Are you asking could it 14 suggest alternative therapeutic approaches? 15 Q. Yes, that's better. 16 A. It isn't obvious to me what 17 those would be, no. 18 Q. All right. Does anybody have 19 a reason for the hypothesis that the majority of 20 the serotonin that's in the synaptic cleft is 21 either transported to the postsynaptic neuron or 22 is taken back up by the presynaptic neuron? 23 A. Well, as I mentioned earlier, 24 there is no transport into the postsynaptic. Page 115 1 Q. You're right, I'm sorry. 2 A. The interaction with the 3 postsynaptic neuron is thought to be at the 4 surface receptor. The transport back into the 5 presynaptic neuron presumably offers a way of 6 terminating the action of serotonin without 7 having to wait for it simply to diffuse away. 8 Q. Well, do you think that the 9 reuptake by the reuptake side on the presynaptic 10 neuron prevents loss of serotonin from the 11 synaptic cleft? 12 A. The physiologic purpose of the 13 uptake is not thought to be one of preventing 14 loss or preservation, but rather one of 15 terminating the action once the serotonin has had 16 a chance to come in contact with the postsynaptic 17 receptor. 18 Q. Why is there a reason to 19 terminate the action? 20 A. Well, please understand I 21 didn't design the system, but a possible 22 explanation is simply that what one wants to do 23 is send discrete signals, and you want to be able 24 to limit the duration of those signals. Page 116 1 Q. Why would you want to limit 2 the duration of the signals? 3 A. Well, I remind you of the same 4 caveat, that it isn't something I designed 5 because I wanted it to be that way. 6 Q. Why would one or the good Lord 7 want to -- 8 A. That's, you know, probably a 9 guess I would rather not make as to what he or 10 she had in mind. 11 Q. Is there any -- 12 MR. SMITH: He's politically correct, 13 isn't he? 14 MR. HARRIS: Are you going to take the 15 deposition of the guy who did design the system, 16 Paul? 17 Q. Is there any biochemical 18 reason that a discrete message that is terminated 19 is of benefit? 20 A. I assume you're asking is of 21 greater benefit than a message which wasn't 22 terminated, I don't know if I understand what 23 you're asking. 24 Q. Well, it's my understanding Page 117 1 that the system of reuptake, at least in part, is 2 to not preserve serotonin or prevent it from 3 leaving the synaptic cleft, but to do something 4 to limit the message that is being transported to 5 the receptor side. Is that right? 6 A. Yes, I think that's right, to 7 provide for a certain degree of activation of the 8 postsynaptic receptor. 9 Q. Why is that important to have 10 a limit on the activation of the postsynaptic 11 receptor? 12 A. I think all I can do is 13 describe the system as it exists in nature to the 14 best of our understanding without speculating on 15 why it happens to be that way. 16 Q. Okay. And I think -- have we 17 pretty well described the system, at least so 18 far? 19 A. I think the essence of the 20 system has been described. 21 Q. Fluoxetine works on the 22 reuptake receptor site, is that correct? 23 A. That is correct. 24 Q. Is the reuptake receptor site Page 118 1 a physical place on the presynaptic neuron? 2 A. Well, let me again point out 3 that, one, a neuropharmacologist would not use 4 the term receptor in that context, the 5 transporter site is ordinarily referred to as 6 separate from the receptor site. The transporter -- 7 yes, the transporter would be a particular 8 macromolecular complex within the cell membrane. 9 Q. And it would have a particular 10 anatomical location -- 11 A. Yes. 12 Q. -- on the cell membrane, is 13 that correct? 14 A. Yes. 15 Q. And the action of Fluoxetine 16 is to act on that transporter, is that correct? 17 A. To interact with it, yes. 18 Q. So we've got a receptor 19 receiving the serotonin messages, correct? 20 A. That is correct. 21 Q. That we have described on the 22 postsynaptic neuron. 23 A. Yes. 24 Q. And then we've got a Page 119 1 transporter that is drawn on the presynaptic 2 neuron with a circle with an X in it, is that 3 right? 4 A. That is correct. That is not 5 to imply that receptors don't also occur on the 6 presynaptic neuron, however. 7 Q. All right. Would those be 8 receptors of serotonin? 9 A. Yes, there are serotonin 10 receptors also present on serotonin neurons 11 themselves, and these are usually called 12 autoreceptors. 13 Q. What is their function? 14 A. Their function is believed to 15 be to sense the concentration of serotonin in the 16 synaptic cleft, and to regulate the further 17 release and synthesis of serotonin within that 18 neuron. 19 Q. We were going to get to that, 20 because I was going to back up and say, well, 21 what starts the process to begin with, that is 22 the discharge of the serotonin from this storage 23 area out into the synaptic cleft, and is it your 24 testimony that there are autoreceptors that are Page 120 1 located on the presynaptic neuron that affect 2 this procedure and start this procedure? 3 A. I wouldn't use the word starts 4 that procedure, but they certainly do influence 5 that procedure. 6 Q. Would regulate be an accurate 7 term? 8 A. Yes, it would. 9 Q. Can you draw an autoreceptor? 10 A. It will look much like a 11 postsynaptic receptor. 12 Q. Why don't you make it in a 13 star or something -- 14 A. I will. 15 Q. -- a diamond, you know, make 16 it a little -- okay. Does Fluoxetine in any way 17 work on the autoreceptor? 18 A. No, not so far as we know. 19 Q. Does Fluoxetine work in any 20 way, in any manner, on the postsynaptic receptor? 21 A. Fluoxetine does not directly 22 interact with either the presynaptic or 23 postsynaptic receptor. By interacting with the 24 transporter, it alters the amount of serotonin Page 121 1 that interacts with those receptors. 2 Q. But that's an indirect action. 3 A. The action of Fluoxetine on 4 the transporter is a direct action, the 5 consequence of that direct action is an increase 6 in the amount of serotonin which acts on the 7 postsynaptic receptor. 8 Q. The theory in connection with 9 the use of Fluoxetine for treatment of 10 depression, as I understand it, is that some 11 individuals do not have enough serotonin present 12 in the synaptic cleft, is that right? 13 A. That is one theory. 14 Q. Is there any scientific data 15 on why some individuals would have an inadequate 16 amount of serotonin within the serotonin -- 17 within the synaptic cleft, and others would have 18 an adequate amount? 19 A. Well, there are -- there have 20 been many published studies in which scientists 21 have measured the amount of serotonin in brain 22 samples obtained at autopsy from patients who 23 died and who had depression. In relation to 24 patients who died but were not depressed, of Page 122 1 similar -- and they were patients of similar age 2 and sex and so on, there is evidence from some 3 studies that the concentration of serotonin may 4 be reduced in the brains of depressed patients so 5 that there may be less stored serotonin available 6 for release in some depressed patients. 7 Q. Can you give me the -- a name 8 of a study that comes to mind, are those the 9 studies back as early as the '50s and '60s? 10 A. Many of the studies were done 11 quite a number of years ago, yes. 12 Q. All right, we have those. The 13 scientific thought is is that the reason for this 14 deficiency in the serotonin available at the 15 synaptic cleft is by virtue of an inadequate 16 amount of storage in the storage sites that hold 17 serotonin? 18 A. That would be one possible 19 explanation, and that would be the explanation 20 that would be supported by the particular studies 21 that I just mentioned, yes. 22 Q. Are there other explanations 23 as to why some individuals have -- that account 24 for some individuals having less serotonin than Page 123 1 others? 2 A. No, I don't know that there is 3 other explanations that could be supported with 4 data. 5 Q. Has there been any research to 6 determine whether or not diet has an influence on 7 the amount of serotonin available within the 8 storage facilities? 9 A. Yes, there has been such 10 research. 11 Q. And what is the result of that 12 research, as to whether or not diet can be a 13 cause of a shortage of serotonin? 14 A. I think the overall evidence 15 is that dietary changes have been shown to have 16 modest influences on the amount of serotonin. 17 Obviously tryptophan, being the precursor to 18 serotonin, any diet that was grossly deficient in 19 tryptophan would certainly impair the synthesis 20 of serotonin, for example. 21 Q. Have there been any studies of 22 any individuals, humans, that have for some 23 reason or another had a diet that is grossly 24 insufficient of tryptophan? Page 124 1 A. Yes, there are certainly some 2 countries in which the type of protein that's 3 consumed is relatively low in tryptophan, and 4 there can be nutritional consequences as a result 5 of that. The consequences generally, however, 6 are not principally related to serotonin. 7 Tryptophan is required for synthesis of all 8 proteins and it has other functions in the body, 9 so that results of tryptophan deficiency would 10 not necessarily principally be caused by a 11 shortage of serotonin. 12 Q. Certainly those people, by 13 virtue of their insufficient diet, have problems 14 that are other than problems of depression and 15 related to problems with the serotonin system? 16 A. Severe shortage of tryptophan 17 certainly would produce a multitude of problems. 18 Q. Is there any thought that by 19 basis of genetics some of us that may be 20 inherited with an impaired ability to produce or 21 store serotonin? 22 A. That sort of possibility 23 certainly has been considered. I don't believe -- 24 there is not evidence that occurs to me at the Page 125 1 moment that would say that's the major 2 determinant. 3 Q. So what's the major reason 4 that some people suffer from either a lack of 5 serotonin or a serotonin system that makes this 6 neurotransmission? 7 MR. MYERS: I'm sorry? 8 Q. Neurotransmission, incomplete 9 or inadequate in some form. 10 MR. MYERS: I object to the form to 11 the extent you've asked, and maybe I'm just 12 asking, are you saying no serotonin at all? You 13 said lack of serotonin. 14 Q. Well, a lack of available 15 serotonin to create the proper neurotransmission 16 within the serotonin system. 17 A. Please understand, I haven't 18 said there are such people. I have mentioned 19 some evidence that has been published to suggest 20 that, and the reasons to the extent that there 21 are such people, the reasons for that, I think, 22 are not known. One potential reason that would 23 need to be investigated in any individual if this 24 were shown to occur would be something like Page 126 1 dietary restriction, inadequate dietary intake of 2 tryptophan, that would be a possible reason. But 3 is that an actual reason in anybody's case, not 4 that I know of. 5 Q. In other words, the theory, 6 based on these studies back in the '60s, even, 7 maybe as early as the '50s, I don't recall, was 8 that there was less serotonin found at autopsy 9 and at spinal taps of individuals who had met 10 with suicide deaths as opposed to those who had 11 died of natural diseases in that there was a 12 finding that they had less serotonin in their 13 cerebrospinal fluid, is that correct? 14 A. Well, I think you've mixed 15 several types of studies together. 16 Q. Don't let me. 17 A. There have been studies of 18 serotonin contents in autopsy brain samples. 19 These are not necessarily studies in patients who 20 died of suicide, although some of them, I think, 21 were. Patients -- some patients who are 22 depressed do die of suicide, some patients who 23 are depressed die of other causes. And there 24 have been studies that have focused on depressed Page 127 1 patients who died, but not of suicide, in which 2 serotonin content in autopsy brain sample was 3 measured. 4 There have been other studies, 5 which you, I think, are referring to, in which in 6 the cerebrospinal fluid, obtained by spinal tap, 7 there were measurements, but in that case it was 8 not serotonin that was being measured, it was the 9 concentration of 5-HIAA, the serotonin 10 metabolite. And in some of those studies, there 11 were findings that at least in some depressed 12 patients, there was a lower than normal 13 concentration of 5-HIAA in the cerebrospinal 14 fluid, and in some studies there is evidence that 15 this is particularly true of patients who are 16 suicidal as opposed to patients who are not 17 suicidal. So there are several different kinds 18 of studies that have been done. 19 Q. And it's those studies that 20 form the sole basis in humans that depression may 21 be related to low levels of serotonin or low 22 levels of its metabolite -- or measured -- or low 23 levels of serotonin, just leave it at that. 24 MR. MYERS: I object to the form only Page 128 1 to the extent you used the term sole basis. I 2 don't know if anybody said that yet. But if you 3 can answer, answer, Doctor Fuller. 4 A. I would answer by saying no, 5 that is not the sole basis for the interest in 6 the belief that serotonin is important in 7 depression. 8 Q. Okay. What other evidence is 9 there? 10 A. The other -- an important line 11 of evidence, separate and distinct from those, 12 was the findings that drugs which were effective 13 in treating depression, including the monoamine 14 oxidase inhibitors and the tricyclic -- so-called 15 tricyclic antidepressant drugs, which are uptake 16 inhibitors, the fact that they were effective in 17 treating depression, alleviating symptoms of 18 depression, coupled with the knowledge that they 19 did affect serotonin, they didn't affect 20 serotonin specifically, they affect other 21 monoamines as well, but among the monoamines they 22 will affect is serotonin. And so that knowledge, 23 when it's interpreted as further evidence that 24 implicated serotonin as an important Page 129 1 neurotransmitter in depression, again it does not 2 necessarily mean that a low serotonin 3 concentration is the cause of depression, but it 4 supports the idea that if you can enhance 5 serotonin function, you can alleviate depressive 6 symptoms. 7 Q. And the theory is that you 8 enhance serotonin function by increasing the 9 serotonin available within the synaptic cleft? 10 A. By increasing serotonin in the 11 synaptic cleft. I wouldn't use the word 12 available in that sentence if it were me. 13 Q. Why? 14 A. I don't understand what the 15 meaning of it is. The amount of serotonin in the 16 synaptic cleft is increased. 17 Q. All right. And that is the 18 amount that is available for neurotransmission is 19 that serotonin that's within the synaptic cleft? 20 A. That is not a statement I 21 would make, because to me saying the amount 22 available, I would consider the amount here as 23 the amount available, it isn't the amount being 24 used at that instant, but it is still available Page 130 1 for neurotransmission. 2 Q. But it's the amount that's 3 being used that's important in neurotransmission? 4 A. That's why I would say that 5 and not say the word available, yes. 6 Q. But neurotransmission doesn't 7 occur in any other location other than at that 8 spot within the synaptic cleft where the 9 receptors are located? 10 A. No, that's not accurate. As I 11 explained earlier, there can be neurotransmission 12 at anatomic sites where there are not synaptic 13 junctions, that is there can be neurons that have 14 serotonin receptors and that are affected by 15 serotonin in places other than where there is a 16 tight synaptic junction. But I think the general 17 idea that you meant probably is correct. 18 Q. In those other locations where 19 there is neurotransmission involving serotonin 20 because there are other serotonin receptors, how 21 does the serotonin get to the locations where 22 those other serotonin receptors are located? 23 A. Once it is released out of the 24 serotonin terminal, again, it can be diffused Page 131 1 through the biological fluid. 2 Q. Is it picked up through the 3 blood brain barrier? 4 A. Serotonin doesn't cross the 5 blood brain barrier, but I don't think what we're 6 talking about here involved the blood brain 7 barrier anyway. 8 Q. Is serotonin present in 9 cerebrospinal fluid? 10 A. There is very little serotonin 11 in cerebrospinal fluid, that's why what is 12 measured in cerebrospinal fluid is the 13 metabolite, 5-HIAA. 14 Q. Is the reason that there is 15 very little in spinal fluid because most of the 16 serotonin is used in neurotransmission, and the 17 rest of it, almost all of the rest of it is 18 stored? 19 A. Probably the reason that there 20 is so little in the cerebrospinal fluid is that 21 it is metabolized once it is released from the 22 storage granules, it is metabolized before it 23 reaches the cerebrospinal fluid. So it is 24 converted to 5-HIAA before it reaches the Page 132 1 cerebrospinal fluid. 2 Q. Okay. Is this autoreceptor 3 the only thing on the presynaptic neuron that 4 causes the presynaptic neuron to release 5 serotonin into the synaptic cleft? 6 A. Probably not. 7 Q. What would be the other causes 8 of the storage area releasing serotonin into the 9 synaptic cleft? 10 A. The serotonin neuron is -- the 11 release of serotonin can be influenced by 12 synaptic messages that the serotonin neuron is 13 receiving from the many other neurons that may 14 input to it. Some of those inputs are occurring 15 back at the serotonin cell body, and some are 16 occurring very likely at the nerve terminal, 17 where for example may be other receptors, that 18 I'll try to draw a little bit differently, that 19 are responding to still other neurotransmitters. 20 There might be other neurons coming in here that 21 would tell this serotonin neuron things about how 22 much serotonin it should be releasing. 23 Q. So are you saying that another 24 receptor on the serotonin neuron might be Page 133 1 receiving messages from dopamine, epinephrine or 2 other neurotransmitters that would cause -- that 3 would affect the release of serotonin? 4 A. Yes. 5 Q. From the storage area? 6 A. Yes. 7 Q. All right. Has there ever 8 been any studies or any measurement as to the 9 comparative effect of receipt of messages from 10 other neurotransmitters, such as dopamine or 11 things of that nature, versus the primary 12 autoreceptors that receive messages from 13 serotonin at the presynaptic cleft as to what 14 influence one is versus the other quantitatively? 15 MR. MYERS: On the the release of 16 serotonin? 17 MR. SMITH: Yes. 18 A. Almost certainly that -- first 19 of all, just because I mentioned the autoreceptor 20 first doesn't make it the primary influence, I 21 think. One should begin with an assumption that 22 any of the receptors that exist might influence 23 serotonin release, and the relative importance 24 probably varies with different circumstances. Page 134 1 During a period when the serotonin neuron is 2 relatively silent and not releasing much 3 serotonin, the autoreceptor probably is of little 4 importance. It becomes more important during 5 periods when there is increasing amounts of 6 serotonin in the synaptic cleft. 7 Q. Why? 8 A. Because it is responding to 9 serotonin in the synaptic cleft. If there are 10 low amounts out there, it wouldn't be responding. 11 A. Okay. 12 Q. So that -- I don't think it is 13 exactly meaningful to talk about relative 14 importance because theoretically that relative 15 importance would vary depending upon the 16 circumstances surrounding that neuron at any 17 given time. 18 Q. All right. What if the neuron 19 was acting normally in the storage of the 20 serotonin -- the storage bodies were acting 21 normally, and all the autoreceptors and other 22 receptors that regulate the input of serotonin 23 into the synaptic cleft were working normally and 24 you added Fluoxetine, where you prevented the Page 135 1 reuptake of serotonin, what would occur in that 2 instance? 3 A. I think there would be an 4 increased amount of serotonin in the synaptic 5 cleft, which would then begin to activate the 6 autoreceptor as well as the postsynaptic 7 receptor, and this activation would then begin to 8 slow down the amount of serotonin released and 9 limit the extent to which this increase was 10 occurring out here, and limit the extent to which 11 neurotransmission was then occurring. 12 Q. Is that what's known as down 13 regulation, Doctor Fuller? 14 A. No, that is not what's meant 15 by down regulation in the sense that that term is 16 ordinarily used. 17 Q. Is this term -- is this 18 situation where you have a normal functioning 19 neuron and you have a theoretically normally 20 functioning serotonin system, and you add 21 Fluoxetine, what effect -- have you just 22 described what the effect would be on the system 23 by addition of Fluoxetine? 24 A. Does that make any sense? Page 136 1 MS. ZETTLER: I spaced out. 2 A. That's what I just did. 3 MR. MYERS: I think he just told you. 4 A. That's what I just did. The 5 point is that what most people mean by down 6 regulation refers to something different than 7 that. 8 Q. All right. Is there any way 9 to know by any independent test or diagnostic 10 procedure whether or not an individual's 11 serotonin system, as we have described, is 12 actually working correctly or incorrectly? 13 A. There are procedures that 14 people are using in an attempt to learn that. 15 The extent to which that is possible is -- let's 16 say it ought to become possible to do that more 17 confidently in the future. 18 Q. Do you know of anybody at Eli 19 Lilly and Company that's working on that? 20 A. You're specifically still 21 referring to studies in humans? 22 Q. Yes. 23 A. No, I don't know of anyone. 24 Q. Is anybody at Eli Lilly and Page 137 1 Company working on that with respect to animals? 2 A. Yes, certainly in a broad 3 sense. 4 Q. But not in the specific sense. 5 A. Maybe you should restate the 6 question to be sure I am answering it as 7 precisely as I can. 8 Q. Is anybody working on any way 9 to determine whether or not any particular 10 individual or animal has a serotonin system that 11 is working in the correct manner? 12 A. We are certainly doing studies 13 in animals to determine the functionality of 14 serotonin systems, I don't think of it in terms 15 of something being correct or something being 16 incorrect. 17 Q. Is there anybody at Eli Lilly 18 working on animals to try to devise a test to see 19 whether or not an animal serotonin system is 20 functioning where the proper amount of serotonin 21 is being stored, the proper amount of serotonin 22 is being released into the synaptic cleft, the 23 proper amount of serotonin is being reuptook -- 24 reuptaken into the presynaptic neuron, and the Page 138 1 autoreceptors and transporters are working 2 properly? 3 A. I don't understand who would 4 be defining properly in that case. 5 Q. Or working in a way that would 6 be expected or that is understood to be normal. 7 A. It's possible to make 8 measurements in animals to ascertain how the 9 serotonin system is working. I don't know how 10 you establish what is normal and what is proper. 11 Q. Well, to where the animal is 12 not exhibiting any signs that are normally 13 associated with serotonin deficiency. 14 A. Well, so far as I know, none 15 of the animals that we worked with are exhibiting 16 any signs of serotonin deficiency, so that 17 therefore anything we find out about the 18 functionality of their serotonin neurons would be 19 relevant to the question you posed. That is not 20 the way I look at it, but that may be the way you 21 look at it. 22 Q. Maybe I put it wrong, and 23 maybe I'm not being as articulate as I should be. 24 I'm simply wanting to know, Doctor Fuller, if Page 139 1 anybody at Eli Lilly and Company is working on a 2 way to determine whether or not the serotonin 3 system is functioning in a manner that would call 4 for normalcy, if I made myself clear. If I 5 havn't, tell me where I'm messing up. 6 A. All of the animals that we 7 study would, I assume, fall within your limits of 8 normalcy, that is we don't choose animals that 9 are abnormal. 10 Q. But you can do things to those 11 animals that would affect their serotonin system, 12 can you not? 13 A. Yes. 14 Q. And you can observe changes of 15 some sort in their serotonin system by virtue of 16 things you've done to alter their serotonin 17 system, is that correct? 18 A. Yes. 19 Q. What changes can you observe? 20 A. Well, there are a variety of 21 changes that can be observed by affecting 22 serotonin systems, I mean much of the research 23 that I and others have done for the thirty-one 24 years that I have been there and the various Page 140 1 times that others have been there have been 2 concerned with drugs that modify serotonin 3 functioning, and, you know, the number of 4 different effects that have been looked at is -- 5 there's lots of things that we've looked at over 6 the years in response to modifying serotonin 7 functioning with drugs, for example. 8 Q. What is down regulation? 9 A. Down regulation is a term that 10 is ordinarily used to mean changes in some 11 constituent of a biological system, such as a 12 receptor, which occurs in response to some 13 prolonged alteration or perturbation of that 14 system. 15 Q. Is it correct that in your 16 early studies on Fluoxetine and animals that you 17 found a down regulation in the serotonin 18 receptors? 19 A. Are you asking -- when you 20 refer to your studies, are you asking about 21 studies in my laboratory or studies at Eli Lilly 22 and Company in general? 23 Q. At Eli Lilly and Company in 24 general. Page 141 1 A. Yes, there were such studies 2 that were conducted that examined changes in 3 serotonin receptors as measured by radioligand 4 binding. 5 Q. This would be these receptors 6 here that receive -- that are primarily 7 responsible for receipt of the serotonin, is that 8 correct? 9 A. Well, in radioligand binding 10 studies of this sort, these are done in brain 11 homogenates, so there would be no distinction 12 between where those receptors were, whether they 13 were pre- or postsynaptically located. Probably 14 on a percentage basis, by far the majority, 15 quantitative majority of those receptors measured 16 would have been postsynaptically located, but one 17 would not distinguish those by presynaptic 18 autoreceptors. 19 Q. So the down regulation was 20 found only in studies that were done in vitro, in 21 the test tube? 22 A. No. The studies were done in 23 animals, by administering Fluoxetine to animals. 24 But then to measure the receptors, you have to Page 142 1 take the brain out of those animals and measure 2 the radioligand binding to it in the test tube, 3 so the final measurement is in the test tube. 4 But that is the sort of study that most people 5 would call an in vitro study. 6 Q. All right. And what's the 7 implication of down regulation, Doctor Fuller? 8 A. In general, when receptors are 9 exposed to an increased amount of transmitter, it 10 would not be unusual for them to down regulate, 11 and if they are exposed to a reduced amount of 12 neurotransmitter, it would not be unusual for 13 them to up regulate. 14 Q. Were there ever any studies 15 done that demonstrated receptors up regulating in 16 response to an inadequate source of serotonin? 17 A. Studies by whom? 18 Q. Anybody. 19 A. Anybody. Yes, there have been 20 such studies. 21 Q. And can you give me where 22 those studies were done and who did those studies 23 off the top of your head? 24 A. No, I don't think so. I can Page 143 1 tell you the nature of the studies. For example 2 if one liges serotonin neurons with fifty-six or 3 fifty-seven dihydroxytryptomine, there have been 4 studies done indicating that there was an up 5 regulation of serotonin receptors presumably as a 6 consequence of having reduced the amount of 7 serotonin that those receptors were exposed to. 8 But could I remember the authors of such studies 9 right now, I'm embarrassed to say, I can't. 10 Q. Why doesn't, then, down 11 regulation or autoregulation ensure that there is 12 a normal serotonin neurotransmission if the body 13 has a built-in mechanism to account for levels of 14 serotonin that are adequate, too adequate or too 15 excessive or inexcessive? 16 A. Again, I think you're asking 17 me about the design of a system that I didn't 18 design. But I imagine the reason is that up 19 regulation can only compensate to a certain 20 extent, not completely. 21 Q. Could the same be said for 22 down regulation, down regulation can compensate 23 only to a certain extent, not completely? 24 A. That may be true. Page 144 1 Q. Doctor Wong said that in down 2 regulation, I believe it was twenty-five to 3 thirty percent of the effectiveness of the 4 receptor site is reduced. Does that conform with 5 your understanding? 6 A. You would have to tell me what 7 the meaning of the word effectiveness was there. 8 Q. Well, it's my recollection we 9 were in a discussion about whether or not that 10 receptor site, by virtue of shutting down or down 11 regulating, whether it became inactive or totally 12 inoperable, and I think his response was well, 13 whatever it does, it becomes twenty-five to 14 thirty percent less able to receive the excess 15 serotonin. 16 MR. MYERS: Before he answers, let me 17 object to the form because I don't know if that's 18 exactly precisely what he said. 19 MR. SMITH: I didn't say it was 20 exactly precisely what he said. I made it clear 21 it's my recollection that he said something 22 approximately like that. 23 MR. MYERS: That's the premise of your 24 question, you stated it as as fact. Page 145 1 MR. SMITH: I didn't state it as a 2 fact. 3 MR. MYERS: Yes, you did. 4 MR. SMITH: No, I didn't. 5 MR. MYERS: Let's see if he agrees or 6 not. If you know the answer, tell him, Doctor 7 Fuller. 8 A. I could -- since I didn't hear 9 that conversation, I couldn't say anything 10 relative to it, but I could comment in general on 11 what down regulation means in terms of function. 12 Q. All right. 13 A. In general, what one is 14 measuring in these studies is the actual number 15 of receptor sites, and there is -- there might 16 be, for example, a twenty-five percent reduction 17 in the number of receptor sites. 18 Q. Does that mean they're just 19 gone? 20 A. At that time, yes. 21 Q. Forever? 22 A. No. 23 Q. Okay. 24 A. Receptors are dynamic things, Page 146 1 they are constantly being degraded and 2 synthesized. But the receptors that are in my 3 brain today are not the same receptors that were 4 there ten years ago, or even less. So that 5 receptors are constantly being formed and being 6 degraded, and being replaced. When down 7 regulation occurs, there simply at that point in 8 time are fewer receptors than there had been at 9 the initiation of whatever event you used to 10 cause the down regulation. That is not 11 synonymous with saying there's a twenty-five 12 percent reduction in function that might or might 13 not change in parallel. 14 Q. It could -- you're saying it 15 might or might not, so you mean it could 16 potentially result in a twenty-five percent loss 17 of function of neurotransmission? 18 A. The presumption would be that 19 there would be some reduction in 20 neurotransmission, and it could turn out probably 21 to be exactly the same percentage as to change in 22 receptor sites, yes. 23 Q. How long does it take for down 24 regulation to occur? Page 147 1 A. Down regulation of what, 2 where? 3 Q. Of the serotonin system or of 4 the receptor. It's the receptors themselves that 5 are down regulating, is it not? 6 A. The question would have to 7 pertain to a particular neuron system, that is 8 the different serotonin pathways in the brain, if 9 you do some alteration they may not all respond 10 the same way, and they may not all respond at the 11 same rate. So that question would have to 12 address -- would have to be more specific. But 13 in general I could answer by saying that receptor 14 changes of this sort, adapting changes in 15 receptors typically with neurotransmitters, would 16 occur within a few weeks. 17 Q. Could it occur in a shorter 18 time? 19 A. There may be circumstances 20 where it occurs in a shorter time, yes. 21 Q. What would be circumstances 22 that would cause it to occur in a shorter time? 23 A. There are simply some systems 24 that may adapt in a shorter time than others, I Page 148 1 don't know that one would refer to that as a 2 cause. 3 Q. Let me see if I understand. 4 Down regulation occurs in connection with the 5 application of Fluoxetine to the serotonin 6 system. When you have -- when you initially 7 apply serotonin or apply Fluoxetine to the 8 transporter sites, you have an increased amount 9 of serotonin in the synaptic cleft. This 10 increased amount of serotonin in the synaptic 11 cleft is picked up by the autoreceptors, and 12 potentially other receptors, and they send a 13 message to the storage site to reduce the 14 production and distribution of serotonin. Am I 15 correct so far? 16 A. I think you're mixing up two 17 different adapting responses. The adaptive 18 response in the synthesis and release of 19 serotonin is a very early event that doesn't 20 involve changes in receptors. That isn't 21 ordinarily referred to as down regulation. In 22 addition to that event, there are other changes 23 which typically occur at longer time intervals, 24 and which do involve changes in receptors, and Page 149 1 which are referred to as down regulation and up 2 regulation. So the beginning of your question, I 3 think, mentioned down regulation, but then you 4 began talking about was not down regulation, but 5 a different kind of adaptive response, so it 6 wasn't clear to me, no. 7 Q. All right. Maybe I'm 8 confused. Down regulation occurs when, in 9 response to something, less serotonin is being 10 produced, is that correct? 11 A. No, down regulation would not -- 12 down regulation of serotonin receptors would not 13 ordinarily occur when there's less serotonin 14 being produced. Down regulation of serotonin 15 receptors would ordinarily occur when they are 16 being exposed to more serotonin. 17 Q. Okay. So the receptors 18 themselves may be reduced physically by as much 19 as twenty-five percent in down regulating to 20 adapt to the excessive serotonin that's being 21 produced? 22 A. That's correct. 23 Q. To not being produced, to 24 which they are being exposed to? Page 150 1 A. That's correct. 2 Q. And that affects the 3 neurotransmitters at the receptor sites, is that 4 right, that is an effect done by the 5 neurotransmitters -- by the receptors at the 6 receptor sites? 7 A. I would be happy to try to 8 explain it once again, but I have trouble 9 understanding your question. 10 Q. All right. 11 MS. ZETTLER: Can we take a break? 12 MR. SMITH: Yes, let's take a break. 13 (A SHORT RECESS WAS TAKEN.) 14 Q. Is it possible -- I think part 15 of my confusion may be in confusing the process 16 of turnover of serotonin versus down regulation. 17 Could it be that I'm getting those terms 18 confused? 19 A. I think that's possible. 20 Q. Let me see if I can talk my 21 way through it, and you stop me if I'm wrong. 22 Turnover is that process where serotonin is 23 released into the synaptic cleft and the 24 transporters then take that serotonin and return Page 151 1 it into the serotonin neuron for reuse or 2 metabolism, is that right? 3 A. Well, no, I don't think that 4 is the way one would define turnover. 5 Q. Define it for me. 6 A. Turnover would be the overall 7 rate at which serotonin is being made and 8 destroyed, and part of the way in which it's 9 utilized is what you described. 10 Q. Okay. And down regulation is 11 something that occurs only at the receptor sites, 12 it has to do with the response of the receptor 13 sites to the availability of serotonin or 14 overavailability of serotonin in the synaptic 15 cleft? 16 A. Well, down regulation can 17 occur because there has been a change in the 18 number of receptors or because there has been a 19 change in the function of the receptor. 20 Theoretically there can be at least those two 21 different mechanisms by which a process that 22 would be called down regulation might occur. 23 Q. But down regulation isn't -- 24 A. It is ordinarily used to mean Page 152 1 a change in receptors as opposed to something 2 else. 3 Q. And the receptors can be 4 reduced, receptor sites, at least, can be reduced 5 by twenty-five to thirty percent, is that 6 correct, in a down regulation? 7 A. Well, what receptors are you 8 referring to? 9 Q. Those receptors of serotonin 10 on the postsynaptic neurons, and the 11 autoreceptors in the presynaptic neurons, or in 12 other locations on the neurons? 13 A. I don't understand the point 14 you're making by putting a limit on the extent to 15 which that might occur. In theory it could occur 16 outside those limits. 17 Q. All right. And 18 neurotransmission occurs only at the receptor 19 sites? 20 A. The receptor is an integral 21 part of neurotransmission, yes. 22 Q. The message from serotonin 23 won't go from the synaptic cleft into the 24 postsynaptic neuron unless it goes via the Page 153 1 receptor? 2 A. That's right. 3 Q. And how long will these 4 receptors remain in a down regulated state? 5 A. In what conditions, under what 6 circumstances? 7 Q. In any circumstances in which 8 they're in a down regulated state, how long will 9 they remain in a down regulated state? 10 A. If they're down regulated 11 because there's an excess of serotonin, I would 12 assume they would remain down regulated for as 13 long as that excess serotonin persists, however 14 long that is. 15 Q. All right. And could there be 16 a situation where there is an excess serotonin 17 activity indefinitely? 18 A. Could there be, I suppose. 19 Q. And the purpose of Fluoxetine 20 is to block the transmission of serotonin back 21 into the synaptic neuron or to be reuptaken into 22 the synaptic neuron which results in more 23 serotonin remaining in the synaptic cleft, is 24 that right? Page 154 1 A. No, that is not right, as you 2 stated it. 3 Q. How did I state it 4 incorrectly? 5 A. You referred to that uptake as 6 transmission, which is not what transmission is. 7 Q. What is transmission? I 8 thought these were transporters, this site where 9 Fluoxetine worked was on the transporter sites. 10 A. Transport and transmission are 11 two separate and distinct words and terms. 12 Q. All right. Can you define 13 each for me and explain their relationship? 14 A. In the context of this 15 discussion, transport means the translocation of 16 serotonin molecules from outside the neuron back 17 inside of the neuron. Transmission is in 18 reference to the transmission of signals or nerve 19 impulses from this neuron to this neuron. 20 Q. Can the transport of serotonin 21 from the synaptic cleft affect the transmission 22 of serotonin between the neurons? 23 A. The transmission of serotonin 24 between the neurons? Page 155 1 Q. Yes. 2 A. I probably don't understand 3 what you mean. What I referred to was not 4 transmission of serotonin between the neurons, 5 but transmission of a signal which is 6 accomplished by means of serotonin. 7 Q. All right. Then can the 8 transmission of the signal be affected by the 9 transport of serotonin? 10 A. As I think I explained, block 11 of the transport back inside the neuron results 12 in an increased amount of serotonin in the 13 synaptic cleft, and therefore an increased 14 neurotransmission. 15 MR. SMITH: Can you read that back? 16 (THE COURT REPORTER READ BACK THE 17 REQUESTED TESTIMONY.) 18 Q. Okay. Of the message, 19 increase the neurotransmission of the message? 20 A. That isn't something I would 21 say. Neurotransmission is the transmission of a 22 message, I think neurotransmission of the message 23 is probably a redundancy. 24 Q. All right. Page 156 1 (PLAINTIFFS' EXHIBIT NO. 1 WAS 2 MARKED FOR IDENTIFICATION AND 3 RECEIVED IN EVIDENCE.) 4 Q. Doctor Fuller, you have been 5 identified in one of our cases as an expert 6 witness by the defendant. Your name is mentioned 7 on page two. Have you been asked to render any 8 opinions in connection with the lawsuit entitled 9 Fentress versus Shea Communications? 10 A. Not that I remember. 11 Q. Do you know what actually 12 occurred giving rise to the lawsuit, the caption 13 of which is marked as Fuller Exhibit 1? 14 A. No, I don't. 15 Q. Have you seen any medical 16 reports or seen any scientific data in connection 17 with any aspect of Fentress versus Shea 18 Communications? 19 A. Not that I'm aware of. 20 Q. Do you know or have you heard 21 of Mister Ed Stopher, the attorney who designated 22 you as a witness, an expert witness? 23 A. No, I don't think so. 24 Q. Did anybody ask you to render Page 157 1 any type of opinion in that case? 2 MR. MYERS: Before he answers, let me 3 object to the form of the question and just 4 advise you so there's no misunderstanding that 5 whether he knows anything about the Fentress case 6 or not, it is fully expected that he will be 7 asked in that case and maybe in other cases to 8 render testimony, both factual and possibly 9 opinions, concerning the matters that he's been 10 here today testifying about, and that is basic 11 research, neuroscience, with respect to 12 Fluoxetine and serotonin. 13 MR. SMITH: Is that an objection? 14 MR. MYERS: In part. 15 MR. SMITH: What's the other part, a 16 speech? 17 MR. MYERS: A clarification as to what 18 it is that he's going to be expected to do in 19 this or other cases, that and other cases. 20 Q. But up to this time, you've 21 not been asked to render any opinions in this 22 case? 23 A. I don't think so. 24 Q. Do you know of any opinions Page 158 1 that you have in connection with any of the 2 issues that are going to be submitted in that 3 case? 4 MR. MYERS: Before he answers, let me 5 object to the form in that the question is overly 6 broad and vague as to any issues that are going 7 to be submitted in that case because to the 8 extent any issues, as I said earlier, of basic 9 neuroscience, Fluoxetine, serotonin, the matters 10 that he's been examined on here today are at 11 issue in that case. He may give testimony of 12 both factual and opinion nature, and an expert 13 nature, by virtue of his education, training, and 14 experience, in the matters that you're examining 15 him about here today. 16 MR. SMITH: See that's the problem, we 17 haven't had an opportunity to review any type of 18 report or written opinion as we've been requested 19 in connection with Doctor Fuller's testimony in 20 that case. 21 MR. MYERS: Right. Well, the fact 22 that a witness or this witness or anybody else is 23 designated an expert does not necessarily mean 24 that he's been asked to sit down and express Page 159 1 certain defined opinions as to matters, however 2 by virtue of his education, training and 3 experience, that in and of itself may qualify him 4 as an expert witness. 5 MS. ZETTLER: Larry, you know full 6 well that Judge Potter has ordered that you are 7 to ask Doctor Fuller or any of the other current 8 or former employees that were listed on that 9 expert list disclosure opinion testimony or 10 elicit from them what types of opinions you're 11 going to ask them at trial so we have the 12 opportunity to interrogate them on and that you 13 intend to elicit from them at trial. So somebody 14 in this room should have an idea of what kind of 15 opinions that are going -- what testimony is 16 going to be asked of Doctor Fuller at trial. 17 MR. BRENNER: Everybody in this room 18 does. The opinion regarding how Fluoxetine works 19 and basic neurotransmission are related to what 20 you have been examining him on all day. There's 21 no hiding here and you may ask him opinion 22 questions. 23 MS. ZETTLER: The fact of the matter 24 is, that if there's opinion that you guys have Page 160 1 tried to elicit from Doctor Fuller at trial that 2 has not been covered during this deposition 3 either by us or by yourself, and he's not going 4 to be allowed to testify at trial. 5 MR. BRENNER: You can make any 6 statement that you want, that's fine, it's on the 7 record. 8 MS. ZETTLER: Are you here on the 9 Fentress case? 10 MR. HARRIS: Can be. 11 MS. ZETTLER: Are you? 12 MR. MYERS: John is a counsel in the 13 Fentress case, he's a counsel in the 14 multi-district cases and he's counsel in other 15 cases. 16 MR. BRENNER: Other cases on which 17 there's a cross notice. 18 MR. MYERS: Your recitation of Judge 19 Potter's order, your second recitation was closer 20 to what it says, but it's not exactly what it 21 says. 22 MS. ZETTLER: Your interpretation -- 23 MR. MYERS: I'm not going do 24 interpret, the order says what the order says. Page 161 1 MS. ZETTLER: Judge Potter clearly 2 said that you are to elicit opinion testimony 3 from Doctor Fuller at the end of our 4 interrogation of him that you intend to ask him 5 at trial or he will be barred. We are to have 6 the opportunity to ask him about facts 7 surrounding that, what he relied upon, et cetera, 8 so there's no surprise here. He's been listed as 9 an expert witness, you claim that you did that 10 just in case you may ask him an opinion question 11 at trial, but Judge Potter's order is clear. 12 MR. MYERS: Well, the order says what 13 it says, so instead of debating it, why don't you 14 ask some more questions. 15 MS. ZETTLER: I would just like to put 16 you on notice that you better elicit what you 17 intend to ask him at trial, and if we don't cover 18 it you will be barred. 19 MR. MYERS: I will rely on what the 20 order says as opposed to your interpretation of 21 the order. 22 MR. HARRIS: Overruled. 23 MR. MYERS: Which part, which side? 24 (PLAINTIFFS' EXHIBIT NO. 2 WAS Page 162 1 MARKED FOR IDENTIFICATION AND 2 RECEIVED IN EVIDENCE.) 3 Q. (BY MR. SMITH) Doctor Fuller, 4 I have handed you a document marked as Fuller 5 Exhibit 2, which appears to be potentially a 6 chapter in a book that was authored by you. Can 7 you review it and see if you can identify what 8 Exhibit 2 is? And I'll tell you, Doctor, going 9 in, that the documents that I'm going to show you 10 are documents that have come from your file. 11 That confidential legend is stamped across each 12 and every page, was stamped by somebody in the 13 legal staff at Eli Lilly and Company. So this is 14 from your file, and that may give you assistance 15 in identifying this document. 16 A. I don't think I need 17 assistance, but I need a reminder of what exactly 18 the question was. 19 Q. Can you identify what's been 20 marked as Exhibit 2? 21 A. Yes, it's something that I 22 wrote. 23 Q. Is that a chapter in a book? 24 A. I believe that's right. Page 163 1 Q. I can't tell from looking, do 2 you recall what book this is from? 3 A. Probably is from Progress in 4 Drug Research. 5 Q. I'm sorry? 6 A. I think it may be from 7 Progress in Drug Research. 8 Q. That's the name of a book, is 9 that right? 10 A. That's right. 11 Q. When was that book published? 12 A. I couldn't tell you that from 13 memory, within the past ten years. 14 Q. Do you recall who the 15 publisher of that book is? 16 A. No, I do not. 17 Q. Do you recall the group of 18 scientists or individuals that published that? 19 A. You mean the editors? 20 Q. Yes. 21 A. No, I don't. 22 Q. Do you recall writing the 23 article? 24 A. Yes. Page 164 1 Q. Would you turn with me to page 2 two of the exhibit, which would be page 3 eighty-six, to the second paragraph, science and 4 drug action. Do you see that? 5 A. Yes, I do. 6 Q. You say there, in about -- I 7 believe it's the third paragraph of page two, of 8 paragraph two -- 9 MR. MYERS: The third sentence, you 10 mean. 11 MR. SMITH: Yes. 12 Q. Third sentence. It says 13 serotonin -- quote, serotonin is stored in 14 granules or vesicles from which it is released at 15 nerve impulse into the synaptic cleft, end quote. 16 Is that correct? 17 A. Yes, that is correct. 18 Q. Is it -- does that sentence 19 mean when we look at exhibit -- well, let's mark 20 this as an exhibit so we can talk about it. 21 (PLAINTIFFS' EXHIBIT NO. 3 WAS 22 MARKED FOR IDENTIFICATION AND 23 RECEIVED IN EVIDENCE.) 24 Q. When we look at Exhibit 3, Page 165 1 which is your drawing, that a nerve impulse has 2 to come down this neuron to kick or to cause the 3 release of serotonin from the storage granule or 4 vesicle -- 5 A. Yes. 6 Q. -- it's not the autoreceptors 7 that cause the release, then, it's the nerve 8 impulse? 9 A. That's correct. 10 Q. Is the nerve impulse, as 11 you're describing, that travels along the neuron, 12 a charge of electrical energy or is that a 13 chemical? 14 A. No, it's an electrical 15 impulse, yes. 16 Q. What causes that electrical 17 impulse? 18 A. Some signal to the neuron from 19 another neuron. Or a spontaneously programmed 20 firing of that neuron. 21 Q. But the firing or the impulses 22 in an electrical firing or an electrical impulse? 23 A. Yes. 24 Q. Which is the movement of Page 166 1 energy, correct? Is that correct? 2 A. I think electricity is a 3 movement of electrons, principally. 4 Q. Which is energy? 5 A. No, I don't think so. 6 Q. A movement of electrons is not 7 energy? 8 A. Electrons is not energy. It's 9 an electrical impulse, I'm not sure either of us 10 are electricians. 11 Q. Is that electrical impulse 12 generated by a chemical reaction? 13 A. It would certainly involve 14 chemical changes. 15 Q. And does involve? 16 A. Yes. 17 Q. And you can tell us as an 18 expert in biochemistry that this movement of 19 electrons that you've mentioned in these neurons, 20 is caused by a chemical reaction or change? 21 A. I would say it involves a 22 chemical reaction. 23 Q. I'm just not clear, Doctor 24 Fuller. I thought earlier that the Page 167 1 autoreceptors, to some extent, or did cause this 2 release of the serotonin from the serotonin 3 granule or vesicles, but from what I read from 4 this book that you authored, that the nerve 5 impulse causes it to be released into the 6 synaptic cleft? 7 A. What I explained earlier was 8 that the autoreceptors can modulate or influence 9 the amount of serotonin that is released from the 10 synaptic cleft, I think I emphasized once or 11 twice that it did not -- the autoreceptors do not 12 initiate the release of serotonin. 13 Q. Okay. It may very well be 14 that I didn't understand it. But the primary 15 impetus from the release from the storage 16 facility is the transmission of the nerve impulse 17 along the neuron, is that right? 18 A. Yes. 19 Q. You say in the last sentence 20 on page eighty-six, these receptors of serotonin 21 neurons are called autoreceptors. The terminal 22 autoreceptors have the physiologic role of 23 sensing the concentration of serotonin in the 24 synaptic cleft, and modulating the further Page 168 1 release and synthesis of serotonin, end quote. 2 Is that what you were explaining just a minute 3 ago? 4 A. Yes, it is. 5 Q. That it's this autoreceptor 6 that modulates the release? 7 A. Yes. 8 Q. Does the autoreceptor have any 9 function in the reuptake or transport of 10 serotonin from the synaptic cleft? 11 A. No, not so far as we know. 12 Q. At least as far as you can 13 tell from a scientific certainty, it doesn't have 14 anything to do with that? 15 A. With the transport, that is 16 correct. 17 Q. You say, beginning on page 18 eighty-seven, about the third sentence, drugs can 19 act directly at postsynaptic or presynaptic 20 serotonin receptors to mimic or to antagonize the 21 action of serotonin. Can you explain to us, 22 please, what you mean by that statement? 23 A. Yes. Referring back to the 24 diagram, I have talked about Fluoxetine, whose Page 169 1 site of action is the transporter. There are 2 also other drugs which act on these receptors, 3 either the postsynaptic receptor or the 4 presynaptic receptor, that is they don't interact 5 with the transporter, they interact directly with 6 the receptor. And they can interact in a way 7 such that they do the same thing serotonin does, 8 they mimic serotonin, or they can actually block 9 the receptor and block the action of serotonin. 10 Q. What drugs are those? 11 A. Well, there are many different 12 agonists and many different antagonists. 13 Q. Such as? 14 A. Direct acting -- I think many 15 of them are listed in the particular chapter you 16 have, as a matter of fact, beginning on page 17 ninety, and continuing through page ninety-three, 18 would be a lot of information for you on 19 agonists. And beginning on page ninety-three, 20 and continuing on to page ninety-four, would be a 21 listing of the number of antagonists. 22 Q. Do these agonists or 23 antagonists have any effect on the serotonin 24 system if you're also using Fluoxetine to block Page 170 1 the transport of serotonin back into the 2 serotonin neuron? 3 A. Sure. They would still be 4 adjuting their effects on these receptors. 5 Q. And could that affect 6 neurotransmission? 7 A. It would affect 8 neurotransmission, yes. 9 Q. Turn to page eighty-eight, the 10 first -- I guess it would be the second full 11 paragraph. You say despite the decreased 12 activity of serotonin neurons, serotonergic 13 neurotransmission is enhanced after uptake in 14 inhibition leading to behavioral and other 15 changes, especially when uptake inhibitors are 16 combined with serotonin precursors, correct? 17 A. Yes. 18 Q. What type of behavioral and 19 other changes are seen when you have a 20 serotonergic neurotransmission which is enhanced 21 after uptake inhibition by Fluoxetine? 22 A. May I read them? 23 Q. Sure. 24 A. To continue with that Page 171 1 paragraph, for example, serotonin uptake 2 inhibitors increase serum corticosterone 3 concentration in rats by increasing 4 corticotropin-releasing hormone secretion from 5 the hypothalamus, and adrenocorticotrophin 6 release from the anterior pituitary. Serotonin 7 uptake inhibitors inhibit muricidal behavior in 8 rats, and potentiate behavioral effects of 9 5-hydroxytryptophan such as head twitch in mice, 10 and the discriminative cue stimulus property of 11 5-hydroxytryptophan in rats. Serotonin uptake 12 inhibitors have analgesic effects in some 13 experimental paradigms and potentiate analgesic 14 effects of opioid drugs. Serotonin uptake 15 inhibitors decrease total food intake in rats, 16 selectively suppress carbohydrate consumption, 17 and suppress stress-induced or insulin-induced 18 hyperphagia in rats. 19 Q. And you have cites there that 20 reflect the particular study that was the source 21 of these findings, is that correct? 22 A. Yes, that is correct. 23 Q. Those studies that you cite 24 for those behavioral and, I guess, physiological Page 172 1 changes that were observed by virtue of the 2 increased serotonergic neurotransmission, are all 3 studies involving animals, specifically mice or 4 rats? 5 A. That is correct. 6 Q. None of those studies involved 7 human beings? 8 A. That is correct. 9 Q. And you don't have -- there 10 are not any scientific studies done on humans 11 that you can cite that support your statements 12 with respect to the behavioral changes found on 13 increased serotonergic neurotransmission, 14 correct? 15 A. The statement has to do with 16 uptake inhibitors, and the -- there are certainly 17 well documented effects of uptake inhibitors in 18 humans, which would include their antidepressant 19 activity, their efficacy in obsessive compulsive 20 disease, and other effects would include their 21 reduction of -- appetite reduction of food 22 intake. There are some neuron studies with some 23 serotonin uptake inhibitors, such as Imiprimine. 24 So there are other studies that refer Page 173 1 specifically to humans that could be cited in the 2 context of this statement. 3 Q. Do you recall whether you had 4 any particular reason for not citing those 5 studies? 6 A. The thrust of this article is 7 not -- this is not a clinical paper, this is a 8 pharmacologic paper, and most of the work that is 9 cited does refer to laboratory animal studies. 10 On page ninety-eight, there are -- in fact 11 there's an entire section which deals with 12 therapeutic uses of drugs that affect serotonin 13 neurons. And then beginning on page ninety-nine, 14 there's a section that is titled clinical 15 nontherapeutic uses of drugs affecting serotonin 16 neurons. And in those sections would be 17 references to the studies that I just mentioned. 18 Q. My question was, was there any 19 particular reason that you didn't cite any human 20 studies in support of the paragraph that you 21 quoted? 22 A. No particular reason. The 23 fact that they are cited later was the 24 predominant reason. Page 174 1 Q. Now on page ninety-one, the 2 last paragraph, you state there is no reason to 3 believe that our understanding of serotonin 4 receptor subtypes is complete at this time, and 5 already evidenced for additional subtypes of 6 serotonin receptors is building. Is that 7 correct? 8 A. That is correct. 9 Q. Then you go on to explain, 10 5HT-1A, 5HT-2, and 5HT-1C receptors have been 11 cloned and eventually the most complete and 12 informative classification of serotonin receptors 13 may be on the basis of protein structure. 14 Correct? 15 A. Yes. 16 Q. On the drawing that we've 17 made, you drew a postsynaptic serotonin receptor 18 and an autoreceptor on the presynaptic neuron, 19 correct? 20 A. Yes. 21 Q. And I believe you mentioned 22 here that there might be other receptors located 23 in other locations other than the neuron, is that 24 correct? Page 175 1 A. Yes. 2 Q. And those would be receptors 3 of serotonin? 4 A. What you're pointing to is -- 5 was designated as a receptor for other kinds of 6 neurotransmitters. 7 Q. Okay. 8 A. What I probably said is that 9 there are -- there can be serotonin autoreceptors 10 on serotonin cell bodies as well on serotonin 11 nerve terminals. 12 Q. But I take it from what I just 13 read on page ninety-one, that there are other 14 receptors of serotonin that are more specific in 15 receiving particular types of serotonin messages, 16 is that right? 17 A. What do you mean by other? I 18 don't understand your question because you used 19 the term other serotonin receptors. If you mean -- 20 Q. Other than those that you've 21 drawn on Exhibit 3. 22 A. No, then that is not correct. 23 These serotonin receptors that occur 24 postsynaptically, and that occur presynaptically Page 176 1 as autoreceptors, are the serotonin receptors 2 that are being discussed in this section on 3 serotonin receptor heterogeneity. The point is 4 that all of these serotonin receptors that occur 5 at different places around the brain and 6 elsewhere are not alike, and if you actually look 7 at the molecular structure where there are 8 serotonin receptors, what you will see is that 9 there are several different subtypes of them, 10 which is what is being discuss here. So what is 11 being discussed here in the chapter under section 12 five point three on serotonin receptor 13 heterogeneity, other than these, are not 14 receptors other than these, but rather this is an 15 elaboration of the nature of those receptors. 16 Q. And you say they possess 17 different molecular architecture? 18 A. Yes, there are a number of 19 different serotonin receptor subtypes which have 20 been cloned, whose amino acid sequence is known, 21 and whose three-dimensional structure has been 22 deduced, and they are -- they have subtle 23 differences one from another. 24 Q. Does that mean they receive Page 177 1 only particular types of serotonin messages? 2 A. They all are responding to 3 serotonin, they are all responding to the 4 identical molecule, but they are different, and 5 therefore drugs which act directly on those 6 receptors may not affect all of those receptors 7 equally. 8 Q. Does that have anything to do 9 with the effects of Fluoxetine on the transporter 10 receptor? 11 A. It has nothing to do with the 12 action of serotonin on the transporter. Don't 13 use the term receptor in conjunction with the 14 transporter. 15 Q. Okay, I'm sorry. 16 A. The relevance to Fluoxetine is 17 that the increased amount of serotonin, then, is 18 acting on different kinds of receptors. For 19 simplicity, I only drew one receptor, as a 20 generic type of receptor. But in fact there are 21 different kinds of receptors, and that's what is 22 being discussed here, so that serotonin is 23 transmitting the signals by means of different 24 kinds of receptors. Page 178 1 Q. I guess what I don't 2 understand is do the different kind of receptors 3 act differently or receive different types of 4 serotonin messages? 5 A. For example they may differ in 6 the concentration of serotonin that is required 7 to activate them. Some of them might be 8 activated by smaller concentrations of serotonin 9 than others, they might be present in different 10 parts of the brain. In one serotonin pathway, 11 for example, there might be 5HT-1A receptors, and 12 in another pathway there might be 5HT-1C 13 receptors, or something of that sort, but they 14 are all responding to serotonin. 15 Q. You say these were discovered 16 by cloning? 17 A. They were -- the evidence that 18 all serotonin receptors are not alike has been 19 accumulating since the mid-1950s. The major 20 advances in understanding that serotonin receptor 21 heterogeneity came in the late 1990s, based on 22 radioligand binding studies of the sort we have 23 talked about before. 24 Q. Did you mean the late 1990s or Page 179 1 the late 1980s? 2 A. Late 1970s is what I really 3 meant. 4 Q. All right. 5 A. The introduction of molecular 6 biological techniques, the cloning of these 7 receptors, has been something that's been 8 occurring during the past ten years, let's say. 9 Q. Have you been involved in that 10 or have other scientists been doing that? 11 A. Yes, I have not been directly 12 involved with that. 13 Q. What do you mean by the term 14 serotonin receptor heterogeneity? 15 A. Just that all serotonin 16 receptors are not created equal. 17 Q. Well, in fact, haven't there 18 been other subtypes of serotonin receptors found 19 even since you authored this paper? 20 A. Yes, there are. 21 Q. Do you know of any additional 22 changes that would affect, and I'm not going to 23 hold you to it because I've just given you the 24 brief opportunity to review it, but does anything Page 180 1 come to you off the top of your head that would 2 be new developments that would affect something 3 that you'd said in any of these chapters? 4 A. There are probably new 5 developments in virtually all of these things. 6 For example, in the sections on agonists and 7 antagonists, there are new ones that have been 8 discovered since then. 9 Q. And that reminds me, I meant 10 to ask you, what are receptor agonists and 11 antagonists? 12 A. An agonist is one of these 13 agents that I mentioned which acts directly at 14 the receptor to mimic the action of serotonin, 15 and an antagonist is something that acts directly 16 on the receptor to block the action of serotonin. 17 Q. And we know that those 18 substances exist? 19 A. Yes. 20 MS. ZETTLER: An agonist works the 21 receptor to mimic and the antagonist blocks it at 22 the receptor? 23 THE WITNESS: Right. 24 Q. Does that have any impact on Page 181 1 the use of Fluoxetine in increasing the level of 2 serotonin available in the synaptic cleft? 3 A. Can you be more specific in 4 asking that so I can understand what you mean? 5 Q. I'm not sure, I mean, would 6 that have an impact on the use of Fluoxetine 7 since Fluoxetine acts indirectly on the receptors 8 and the autoreceptors, by virtue of its affecting 9 the concentration of serotonin in the synaptic 10 cleft, would the fact that there was -- there's 11 agonists and antagonists be of any import? 12 A. Well, an antagonist, for 13 example, would block the effect of that increased 14 amount of serotonin on the receptors that 15 resulted from the uptake inhibition, if that's 16 the sort of thing you had in mind. 17 Q. Well, can antagonists be 18 synthesized? 19 A. Can they be clinically 20 synthesized? That's how they were obtained, yes. 21 Q. Are they known as particular 22 chemicals? 23 A. Well, again, in this chapter, 24 I list a couple of pages of specific antagonists Page 182 1 of different serotonin receptors, and as I 2 mentioned there are still more that have been 3 discovered and studied since the time this was 4 written. 5 Q. Anything else that you see, 6 Doctor, that needs to be added concerning this by 7 virtue of -- or deleted, by virtue of current 8 research? 9 MR. MYERS: With the same caveat that 10 you're not going to hold him to it? 11 MR. SMITH: Yes. 12 Q. I'm not going to make you read 13 it word for word, but anything that this brings 14 to mind? 15 A. There's more research going on 16 all the time in the field of serotonin and 17 pharmacology, so that there clearly would be new 18 findings in virtually every category. But 19 fundamentally, what is said here is still true. 20 (PLAINTIFF'S EXHIBIT NO. 4 WAS 21 MARKED FOR IDENTIFICATION AND 22 RECEIVED IN EVIDENCE.) 23 Q. Can you identify Exhibit 4, 24 Doctor Fuller? Page 183 1 A. Yes. 2 Q. It appears to be a paper that 3 you wrote more recently, in 1991, along with 4 Doctor Fuller and Doctor Robertson? 5 MR. MYERS: This is Doctor Fuller. 6 Q. I mean along with Doctor Wong 7 and Doctor Robertson. 8 A. That's right. 9 Q. Who is Doctor Robertson? 10 A. Doctor Robertson is described 11 on page two, and he's an organic chemist who at 12 the time this was written was director of CNS 13 research and Lilly Research Laboratories, and who 14 since has left Lilly. 15 Q. Where is he now? 16 A. He's at Lygan Pharmaceutical 17 in the San Diego area. 18 Q. Turn to page twenty-two of 19 that article, the last sentence in the middle 20 paragraph. It says the low affinity of 21 Fluoxetine for neurotransmitter receptors is 22 consistent with a lower incidence of 23 anticholinergic side effects, sedation, and 24 postural hypotension in the clinical use of Page 184 1 Fluoxetine compared with tricyclic antidepressant 2 drugs. Is that correct, did I read that 3 correctly even though I butchered the pronouns? 4 A. If the pronunciation isn't 5 included, you read it correctly, yes. 6 Q. You say there that a low 7 affinity of Fluoxetine for neurotransmitter 8 receptors. Did you mean to mean low affinity or 9 no affinity of Fluoxetine for neurotransmitter 10 receptors? I thought it was your statement that 11 Fluoxetine had no effect on any of the 12 neurotransmitter receptors. 13 A. The way one typically studies 14 affinity for neurotransmitter receptors in the 15 studies that were referenced there is through 16 this technique of radioligand binding. And you 17 add the test drug to a test tube increasing 18 concentrations to find out at what concentrations 19 it competes with bonding of the radioligand for 20 those receptors. And Fluoxetine, with all of 21 those receptors mentioned, has very low affinity 22 for it, it means you would have to add very high 23 concentrations before you would get any 24 interference with the radioligand binding. In a Page 185 1 test tube, you can add as much as you want, you 2 can keep pouring in as much as you want. So 3 certainly you can get up to concentrations 4 adequate to inhibit the radioligand binding, but 5 the concentrations that are required in the case 6 of Fluoxetine are very large, and not relevant to 7 the concentrations that would actually occur in 8 an animal or a human that was given with the 9 drug. 10 So low affinity, you know, if 11 the term affinity sometimes means avid binding 12 to, no affinity could be used. The point is that 13 certainly that it doesn't have that high 14 affinity, doesn't act on those receptors at 15 relevant concentrations. 16 Q. So you're being super 17 technically correct when you say the low affinity 18 of Fluoxetine for neurotransmitter receptors, in 19 a scientific sense, but as far as a practical 20 animal or human sense, Fluoxetine is not going to 21 have any affinity in the actual receptors in 22 vitro, is that what you're saying? 23 A. That's what I'm saying. 24 Q. Now if you will turn with me Page 186 1 to page twenty-four, to the last sentence of page 2 twenty-four, it says when Fluoxetine is 3 administered to animals, the serotonin uptake 4 inhibition that results initially is caused by 5 Fluoxetine itself. With time, Fluoxetine is 6 converted to Norfluoxetine, and the long duration 7 of serotonin uptake inhibition following a single 8 dose of Fluoxetine is due at later times to the 9 formation and persistence of Norfluoxetine. Is 10 that correct? 11 A. Yes, that is correct. 12 Q. Possibly you should explain 13 that to us in connection with your diagram, the 14 fact that Norfluoxetine comes into play somehow. 15 A. Well, I'm not sure that the 16 diagram is very helpful explaining that. The 17 situation is that when Fluoxetine is given to an 18 animal or to a human, it is metabolized by a 19 process referred to as N-demethylation, which is 20 described in more detail in this paper, the 21 product being the compound that we call 22 Norfluoxetine. It is simply Fluoxetine with the 23 methyl group removed from the nitrogen in the 24 molecule. And that product, Norfluoxetine, is Page 187 1 virtually identical to Fluoxetine in its ability 2 to block serotonin uptake, and in its selectivity 3 in blocking serotonin uptake, that is it also 4 doesn't block norepinephrine uptake and also 5 doesn't interact with these receptors we talked 6 about. So that when one gives Fluoxetine to a 7 rat, for example, serotonin uptake is inhibited, 8 as I mentioned earlier, for twenty-four hours or 9 more, and if one measured what is in the brain 10 during that time, what you find at the early 11 time, like one hour, is that what is in the brain 12 is mostly Fluoxetine. But with time, the amount 13 of Fluoxetine keeps decreasing, and the amount of 14 Norfluoxetine increases over a period of time. 15 So at twenty-four hours, when uptake is still 16 inhibited, what is present in the brain is mostly 17 Norfluoxetine, so that that uptake inhibition at 18 twenty-four hours is being produced by the 19 metabolite rather than by serotonin -- by 20 Fluoxetine itself. 21 The action is the same, it's 22 just that at early times it is being exerted by 23 the parent drug, and at later times, it's being 24 exerted by the metabolite, principally. Page 188 1 Q. Do you see that as a benefit 2 to Fluoxetine, is that this Norfluoxetine, the 3 metabolite, continues to inhibit serotonin 4 reuptake? 5 A. Well, I believe what this 6 discusses is how that compares to certain other 7 drugs, one of those other drugs being 8 clomipramine, which undergoes metabolism by 9 exactly the same process, N-demethylation. In 10 the case of clomipramine, that metabolite, 11 however, has quite different pharmacology than 12 the parent drug, and it actually is a 13 preferential inhibitor of norepinephrine uptake. 14 So clomipramine starts out in the test tube being 15 a selective inhibitor of serotonin uptake, but in 16 the animal or human, it loses the selectivity 17 because it is converted to this metabolite which 18 has a different action. So relative to 19 clomipramine, one might use the term advantage in 20 Fluoxetine in that it doesn't lose its 21 selectivity as a result of being metabolized by 22 N-demethylation. 23 Q. How long does the inhibition 24 of uptake continue, whether by reason of direct Page 189 1 action of Fluoxetine or the metabolite 2 Norfluoxetine? 3 A. Well, in the case of the rat, 4 there may be some data in here or maybe not. As 5 I mentioned, it persists for at least twenty-four 6 hours after a ten milligram per kilogram 7 intraperotoneal dose of Fluoxetine. 8 Q. Turn to page twenty-six. You 9 have a chapter on stereoselectivity, is that 10 correct? 11 A. Yes. 12 Q. Define stereoselectivity for 13 me, Doctor. 14 A. Well, certain molecules have 15 an asymmetric carbon in them, meaning that of the 16 four -- that carbon has four different 17 substituents attached to it, and they can be 18 attached in different ways so that that molecule 19 exists actually in two isomeric forms, which 20 essentially are mirror images of one another if 21 you could actually look at an individual 22 molecule. And Fluoxetine has an asymmetrical 23 carbon, which means there are two stereoisomers 24 or two enantiomers of Fluoxetine. And this Page 190 1 section deals with the comparative effects of 2 those two separate enantiomers of Fluoxetine as 3 inhibitors of serotonin uptake. 4 Q. Was there any difference? 5 A. In essence, they are equal, 6 there is very little difference in those two 7 isomeric forms of Fluoxetine. 8 Q. Did you find any difference in 9 the side effects? 10 A. What do you mean by side 11 effects? 12 Q. Those side effects that you 13 normally -- that you normally see in connection 14 with Fluoxetine, versus other antidepressants. 15 A. Which is what? 16 Q. Nausea, anxiety, nervousness. 17 A. This doesn't deal with 18 clinical studies, this deals with the laboratory 19 studies with Fluoxetine. 20 Q. Well, do you know of any 21 difference in, quote, side effects between 22 Fluoxetine and its enantiomers? 23 A. No. 24 MR. MYERS: We know what you mean. Page 191 1 A. The properties -- Fluoxetine 2 is made up of two enantiomers. So I think the 3 question is is there any difference in those two 4 enantiomers in terms of their side effects, and 5 not only are they similar in their ability to 6 inhibit serotonin uptake, but they also are 7 similar in their lack of affinity for these other 8 neurotransmitter receptors that we discussed 9 earlier. So, therefore, one would not expect 10 there to be differences in the -- in the side 11 effect profile of those two enantiomers. 12 Q. Do you know of any 13 differences? 14 A. To my knowledge, the two 15 enantiomers have not been separately administered 16 to humans, so there would be no way, no direct 17 data to base that answer on. 18 Q. How about animals? 19 A. I don't know of any 20 differences in animals, no, side effects. 21 Q. In your -- well, what's the 22 question, wasn't there some differences in fluid 23 intake in rats between the two? 24 A. There are small difference, I Page 192 1 think they may be discussed in here or they may 2 not be. They're both effective in reducing 3 fluid. Oh, yes, sure, they're in the table here. 4 Q. What page are you looking at? 5 A. On page twenty-six, in table 6 three, under the comparison of the two 7 enantiomers, the last three parameters listed in 8 the left-hand column all have to do with 9 reduction of intake in different experimental 10 paradynes, and what you see is that the two 11 enantiomers are both effective, and there's not 12 much difference in their ED fifty values. 13 Q. But there is some difference? 14 A. Yes. 15 Q. I noticed in your documents, 16 and I don't think I brought them, but a patent 17 for the enantiomers of Fluoxetine that had been 18 applied for and granted to somebody not 19 associated with Eli Lilly and Company. Do you 20 recall having that in your file? 21 A. Yes. 22 Q. Do you recall that that is a 23 fact, that Lilly does not hold a patent, or 24 anybody associated with Lilly does not hold a Page 193 1 patent to the Fluoxetine enantiomers? 2 A. We do hold a patent to both 3 enantiomers, as a matter of fact. The Fluoxetine 4 is made up of two enantiomers, and we own the 5 patent for Fluoxetine. 6 Q. But can't you patent just one 7 side? 8 A. You could obtain a separate 9 patent on an individual enantiomer, if that's 10 what you're asking. 11 Q. I thought that's what I saw in 12 your file, am I incorrect? 13 A. You may have. 14 Q. And that patent that's held by 15 one of the sides, an individual side, is not held 16 by anybody with Lilly? 17 A. I'm having to guess at the 18 patent you're talking about. 19 Q. I'm sorry, I didn't bring it. 20 MR. MYERS: Doctor Fuller, if you 21 know, tell him, but don't guess. 22 A. I certainly don't know for 23 sure what you saw, so I'm afraid maybe I 24 shouldn't answer. Page 194 1 Q. Do you recall having a patent 2 to one of the sides of the enantiomers in your 3 file at one time? 4 A. Yes. 5 Q. All right. Do you recall 6 whether or not Lilly was the holder of that 7 particular patent? 8 A. The patent I'm recalling was 9 not a Lilly patent. 10 Q. All right. Or somebody 11 employed by Lilly. 12 A. Or somebody employed by Lilly, 13 right. 14 Q. Do you recall why you happened 15 to have that patent in your file? 16 A. I have files of many, many 17 publications on Fluoxetine. 18 Q. I had the unfortunate or 19 fortunate experience of trying to wade through 20 them over the weekend. 21 A. So are you asking is there 22 some different reason I had that than anything 23 else in my files? 24 Q. No, do you recall specifically Page 195 1 how you came into possession of that, did 2 somebody send it to you, was it passed around, 3 was this part of your interest in your research? 4 I just was wondering if you recalled, which you 5 may not recall how it came into your file. 6 A. Clearly the Fluoxetine 7 enantiomers is of interest in my research, as 8 exhibited by this exhibit, and therefore I have 9 tried to collect everything that has been 10 published relative to the two enantiomers of 11 Fluoxetine, and that is one of the things that 12 has been published. I do not specifically 13 remember how I came into possession of that 14 particular document. 15 MS. ZETTLER: Do you remember which 16 enantiomer the patent was on? 17 THE WITNESS: I'm not sure that I do. 18 Q. Turn with me to page 19 twenty-eight. Beginning with the last one and a 20 half words on that page, it says the decreased 21 turnover of brain serotonin after Fluoxetine 22 administration is thought to be due to increased 23 activation of autoreceptors on serotonin neurons 24 whose physiologic role in sensing the Page 196 1 extraneuronal concentrations of serotonin and 2 modulating the further release and synthesis of 3 serotonin. Do you see that? 4 A. I'm sorry, the question? 5 Q. Did you -- have you got that? 6 A. Yes, I see that. 7 Q. Now is that down regulation or 8 is that turnover that you're talking about, or 9 neither? 10 A. It's not down regulation. 11 It's -- yes, the synthesis and utilization of 12 serotonin is decreased, so that's turnover, the 13 turnover the serotonin is decreased. 14 Q. Now turn with me to page 15 thirty. In the first paragraph under therapeutic 16 effects of Fluoxetine in humans, you say uptake 17 inhibition would be expected to enhance 18 serotonergic input to the postsynaptic neurons in 19 many brain regions to which serotonergic 20 terminals project, and it is not possible to know 21 at present which brain regions or which 22 postsynaptic neurons are most important in 23 leading to therapeutic effects in depression. Is 24 that correct? Page 197 1 A. Therapeutic effects in 2 depression. 3 Q. Right. 4 A. That is correct. 5 Q. Explain that to me. Are you 6 saying that there's some neurons that may be more 7 important in regulating mood or depression than 8 others? 9 A. Yes, that's correct. 10 Q. And would these be 11 serotonin-producing neurons exclusively? 12 A. No, this is referring to 13 postsynaptic neurons, so that -- serotonin 14 neurons are very widely distributed in the brain, 15 and those kinds of synaptic connections are 16 present in many different parts of the brain that 17 are concerned with a lot of different things the 18 brain controls, feeding, for example, as we've 19 talked about, certain endocrine functions, and so 20 on. And there are, no doubt, particular parts of 21 the brain where these pathways are what is 22 accounted for the antidepressant activity of 23 serotonin uptake inhibitors. And where exactly 24 in the brain those pathways are, and what the Page 198 1 postsynaptic neurons are, is what is the center 2 of this discussion. As pointed out, at this 3 point, there is not a lot known about that. 4 Q. Is there any effort at Eli 5 Lilly currently under way to determine what the 6 location of those postsynaptic neurons in 7 connection with depression might be or where they 8 may be? 9 A. Well, certainly, yes, in a 10 general sense. The experimental approaches to a 11 question like that, however, are quite limited, 12 and the extent to which we can learn that from 13 studies in laboratory animals is limited. But we 14 are doing all that we can in laboratory animals 15 to help them understand that. 16 MR. SMITH: Let take a quick break. 17 (A SHORT RECESS WAS TAKEN.) 18 Q. Doctor Fuller, as I understand 19 it, both Fluoxetine and Norfluoxetine as 20 metabolite act only at the transport site. 21 A. That's right. 22 Q. Now, do Fluoxetine and 23 Norfluoxetine compete there at the transport 24 site? Page 199 1 A. Do they compete with 2 serotonin? 3 Q. Yes. 4 A. Yes. 5 Q. Do they compete with each 6 other for locations at the transport site? 7 A. I would assume so, yes. 8 Q. Have there been any studies 9 done to determine the rate at which they compete 10 with each other? 11 A. The rate at which they compete 12 with each other, I'm not sure I understand the 13 use of the word rate. 14 Q. Or the manner in which. 15 A. The extent to which they 16 compete with each other? 17 Q. Yes. 18 A. Well, I guess the closest -- I 19 don't think that's an issue that has been 20 addressed or that is particularly relevant, to be 21 honest, but the closest I can think of 22 experimentally that experiments have been done 23 that would address that would be the use of 24 radioactive Fluoxetine as a radioligand to label Page 200 1 that transporter site, and then the addition of 2 nonradioactive Fluoxetine to see the extent to 3 which it competes with that radioligand binding, 4 and yes, those experiments have been done. 5 Q. And what were the results? 6 A. The results were exactly as 7 expected, that is they both have high affinity 8 for that serotonin transport. 9 Q. And this may be way too crude, 10 but let's assume that we have a serotonin 11 transport site upon which Fluoxetine and 12 Norfluoxetine work, and there is -- and they 13 compete for serotonin at that site, correct? 14 A. Yes. 15 Q. And let's say that there are 16 six possible locations for one of those molecules 17 to sit at that transport site, all right? 18 A. Okay. 19 Q. I think we've established or 20 you have explained to us that initially what you 21 have is you have Fluoxetine that comes in and 22 takes up those sites, correct? 23 A. Yes. 24 Q. And serotonin is not able to Page 201 1 get at one of those sites at the table, is that 2 right? 3 A. Yes, that is right. 4 Q. And by virtue of that, the 5 transport of serotonin is blocked at the 6 transport site? 7 A. That's right. 8 Q. Now, as I understand it, 9 Fluoxetine has a relatively short life, is that 10 right? 11 MR. MYERS: Let me object to the form. 12 When you say life -- 13 MR. SMITH: Life as like half-life. 14 A. Relative to what? 15 Q. Relative to Norfluoxetine, the 16 metabolite. In other words, I thought you said 17 we can study clinically the action of Fluoxetine 18 on the brain, and initially we'll see Fluoxetine 19 at a level, then it will start sharply decreasing 20 and the level of Norfluoxetine will start sharply 21 increasing, is that correct? 22 A. There's actually a graph, I 23 think, in the paper we were just looking at, if 24 we wanted to look at it, but -- Page 202 1 Q. Well, am I generally correct, 2 that the Fluoxetine gets gone pretty quick and is 3 replaced by Norfluoxetine? 4 A. I don't know what pretty quick 5 is to you. 6 Q. What is it to you? 7 A. The rate at which Fluoxetine 8 gets gone to me looks very much like this. 9 Q. See, I'm tricking you, Doctor 10 Fuller, I have you in my grip, you're starting to 11 use my terms. 12 A. These are brain concentrations 13 of Fluoxetine and brain concentrations of 14 Norfluoxetine. 15 Q. Okay. We're on Exhibit 4, 16 page twenty-eight, is that right? 17 A. Yes, that's right. 18 Q. And according to the graph, 19 the Fluoxetine starts dropping off, but it's 20 replaced by the Norfluoxetine, that starts 21 increasing, is that right? 22 A. Norfluoxetine increases, I 23 don't know if I would use the word replace. 24 Q. It increases, and Fluoxetine Page 203 1 decreases. 2 A. During this period of time, 3 that's correct. 4 Q. But during this period of 5 time, as I understand it, the level of uptake 6 inhibition of serotonin remains constant, is that 7 right? 8 A. That's roughly correct. 9 Q. All right. So you may have 10 had five places at the transport site that were 11 occupied by Fluoxetine, let's say two places were 12 occupied by serotonin, is that correct, I mean 13 could that be possible that some serotonin would 14 still be being transported even in the presence 15 of Fluoxetine, or does Fluoxetine totally block 16 the transport site? 17 A. At some concentration, that 18 will totally block. 19 Q. How about a therapeutic 20 concentration, in either animals or humans, is it 21 a total blockage? 22 A. I don't know what you mean by 23 a therapeutic concentration in animals. 24 Q. Then a therapeutic Page 204 1 concentration in humans. 2 A. In humans there's no direct 3 way of assessing the extent of blockade of 4 serotonin uptake in the brain. 5 Q. Do you think it's going to be 6 complete at the transport site, in other words do 7 you think that all eight of these seats at the 8 transport site table are going to be occupied by 9 Fluoxetine and none by serotonin? 10 A. I don't honestly think there's 11 a serotonin transport table. 12 Q. I'm just trying to use an 13 illustration. 14 A. I think there can be 15 graduation of inhibition of serotonin uptake all 16 the way up to a hundred percent, and what is 17 happening in the human brain at the doses of 18 Fluoxetine that are used in the treatment, I have 19 no way to know the exact percentage of uptake 20 inhibition. 21 Q. Would it be a reasonable 22 scientific assumption that in the majority of 23 humans taking Fluoxetine, that the serotonin at 24 some or many sites, the transport sites of Page 205 1 serotonin are totally occupied by Fluoxetine? 2 A. It's a possibility. 3 Q. All right. Now as I 4 understand it, using this same analogy, 5 Fluoxetine is going to start leaving these sites -- 6 A. Well -- 7 Q. -- at some point. 8 A. Well, this is a dynamic event. 9 Molecules of Fluoxetine are coming and going all 10 the time, and so are molecules of serotonin. 11 Q. And at some point, the 12 molecules of Fluoxetine are not coming in at the 13 rate that they were earlier, but you start 14 getting a higher rate of the molecules of its 15 metabolite, Norfluoxetine, is that right? 16 A. Well, I think you're going 17 back and forth from a clinical setting to this 18 animal experiment, and you may be -- I'm not sure 19 I understand what you're getting at. In this 20 animal experiment, there's a single dose of 21 Fluoxetine that is given. 22 Q. Uh-huh. 23 A. And these are the amounts of 24 Fluoxetine, Norfluoxetine, that are present at Page 206 1 different times. In humans, in the treatment of 2 depression, of course daily doses of Fluoxetine 3 are given. 4 Q. I understand that. 5 A. So there is more or less a 6 steady amount, whatever that is, of Fluoxetine 7 and Norfluoxetine, so that in a therapeutic 8 setting, probably some of these transport sites 9 would be occupied by Fluoxetine and some would be 10 occupied by Norfluoxetine. 11 Q. Depending on the time of day 12 or the time that the patient took the particular 13 dose? 14 A. Yes, there would be some 15 variation during the time of day, but in fact it 16 would be relatively similar through all the 17 twenty-four hour period. 18 Q. I guess my question is, at 19 some point you're going to have Fluoxetine and 20 Norfluoxetine and serotonin all three competing 21 for sites -- 22 A. Yes, yes. 23 Q. -- at the uptake spot? 24 A. Yes. Page 207 1 Q. There is a limited amount of 2 seats at the uptake spot, and these molecules are 3 going to attach in a limited amount, is that 4 right? 5 A. Yes. 6 Q. And they're going to compete, 7 the three of them, each for a particular seat at 8 the site? 9 A. It would be a trivial 10 scientific exercise. Knowing the affinity of 11 each of these things for the serotonin 12 transporter, one could easily model the exact 13 occupancy at any concentration, any relative 14 concentration you wanted to model. But I don't 15 think that would help you understand anything 16 about the therapeutic effect of Fluoxetine to do 17 that. 18 Q. Well, is the therapeutic 19 effect of Fluoxetine the same as the therapeutic 20 effect of Norfluoxetine, its metabolite? 21 A. Yes, because they both inhibit -- 22 so far as we know, because they both inhibit 23 serotonin uptake. 24 Q. In equal affinity? Page 208 1 A. Well, as we've just looked, in 2 Exhibit 4, with -- maybe we didn't look at that, 3 this paper, I'm sorry. This only compared the 4 enantiomers, it didn't compare the Norfluoxetine. 5 But similar comparisons have been made, and they 6 were essentially equal, yes. 7 Q. All right. 8 MR. SMITH: Does anybody insist that 9 my Fluoxetine table, my transport site table, be 10 attached as an exhibit? 11 MR. MYERS: Only if I can mark it 12 confidential. 13 MS. ZETTLER: Paul, wrong, you 14 established the half-life between Fluoxetine and 15 Norfluoxetine. 16 Q. Is there a difference in the 17 half-life between Fluoxetine and Norfluoxetine? 18 A. By half-life, you're referring 19 to the time it takes for the levels in some 20 place, such as plasma or brain, to disappear? 21 Q. Yes. 22 A. Yes, there is a difference. 23 Q. What is that difference? 24 A. Well, what place are you Page 209 1 talking about? 2 Q. Brain tissue. 3 A. Of what species? 4 Q. Humans. 5 A. I have no idea. 6 Q. Rats? 7 A. Rats, I don't have the half 8 lives memorized, but it's obviously roughly, I 9 don't know, a few hours for Fluoxetine, and 10 several hours for Norfluoxetine. I imagine those 11 numbers have been calculated in some 12 publications, but they aren't particularly useful 13 to me. 14 Q. I seem to recall literature to 15 the effect that if Fluoxetine or Norfluoxetine 16 has a longer half-life than other 17 antidepressants, and there's cautions about 18 administering other medications quickly after 19 discontinuing Fluoxetine, by virtue of the long 20 half-life of Fluoxetine or Norfluoxetine, which 21 means that it continues to be present in an 22 individual system for a period of time after 23 discontinuance of administration of the drug. Do 24 you recall literature to that effect? Page 210 1 A. You're referring now to 2 clinical literature, yes. 3 Q. All right. And that's what 4 I'm speaking of when I'm talking about long 5 half-life. Is it Norfluoxetine that has a long 6 half-life or Fluoxetine? 7 A. Norfluoxetine, plasma half 8 lives in humans are longer for Norfluoxetine than 9 they are for Fluoxetine. 10 Q. Can you quantify that? 11 A. No, I don't remember those 12 numbers, but it's several days for Norfluoxetine, 13 and it's a shorter time for Fluoxetine. 14 MS. ZETTLER: And you don't know what 15 they are in brains of humans? 16 THE WITNESS: In human brains, how 17 would you determine that? 18 MS. ZETTLER: I don't know, you're the 19 expert, Doctor. I'm asking whether or not 20 somebody can tell that, tell what the half-life 21 of Fluoxetine is in the human brain? 22 MR. MYERS: He answered that before, 23 he was talking about rats before. 24 THE WITNESS: The question is, is Page 211 1 there a way of determining Fluoxetine in human 2 brains? 3 MS. ZETTLER: The half-life in the 4 human brain. You just gave us kind of a 5 description of the half-life in plasma. 6 THE WITNESS: There is no way to 7 obtain human brain tissue for a study like that 8 short of autopsy samples or something of that 9 sort, which wouldn't be a way that such 10 information should be obtained, I don't think. 11 Plasma half-life is what one measures in humans. 12 MS. ZETTLER: And the plasma half-life 13 of Fluoxetine and Norfluoxetine in humans is 14 similar to at least the comparative half-lives 15 you described for us in rat brains? 16 THE WITNESS: No, they're longer, 17 the half-lives are longer in human plasma than 18 rat plasma. 19 MS. ZETTLER: Both half-lives? 20 THE WITNESS: Both half-lives. 21 MS. ZETTLER: How about the 22 comparitor? 23 THE WITNESS: In both species, the 24 half-life of Norfluoxetine is longer than the Page 212 1 half-life of Fluoxetine. 2 MS. ZETTLER: Thank you. 3 (PLAINTIFFS' EXHIBIT NO. 5 WAS 4 MARKED FOR IDENTIFICATION AND 5 RECEIVED IN EVIDENCE.) 6 Q. Take a second, if you would, 7 Doctor Fuller, to read Exhibit 5. 8 A. (Witness complies.) 9 Q. Are you having difficulty 10 reading that, Doctor, by virtue of the stamp 11 that's on there? 12 A. No, I can read it. 13 MR. MYERS: Nice try. 14 MR. SMITH: I'm fussing about the 15 stamp, not anything else. 16 Q. Have you had an opportunity to 17 review Exhibit 5? 18 A. Yes, I have. 19 Q. Do you recall authoring 20 Exhibit 5? 21 A. Well, it obviously had been 22 attached to something which isn't attached, and 23 that would have helped me greatly in knowing what 24 this was about. Page 213 1 Q. I couldn't find specifically 2 if it had been attached to something, Doctor 3 Fuller, because there wasn't anything attached to 4 it when I got it. 5 A. It appears to be a review of 6 some manuscript, and I referee officially 7 probably at least one manuscript a week for 8 scientific journals, and more than that for other 9 authors. So for me to remember specifically what 10 this referred to back five years ago, almost is 11 probably beyond my capabilities. 12 Q. Can you tell me who Charles 13 and Dan are? 14 A. I could only guess at who 15 Charles and Dan are. 16 Q. In the context of what you've 17 written there, can you make a pretty educated 18 guess concerning who Charles and Dan would be? 19 A. I think I can, but I might 20 miss. 21 Q. That's fine. 22 A. Probably Charles Beasley and 23 Dan Masica. 24 Q. Is that your writing out there Page 214 1 to the left? 2 A. No, I don't think so. 3 Q. Do you recall whether or not 4 you made the underlining and the bracket notation 5 on page one? 6 A. No, I certainly don't control 7 that, recall that. 8 Q. You say beginning with page 9 two, with paragraph two, the second sentence, the 10 idea of serotonin uptake inhibitor is to block 11 the inactivation uptake of neurotransmitter 12 released into the synaptic cleft, thereby 13 enhancing its action on postsynaptic receptors 14 and increasing serotonergic transmission. How do 15 you know -- this is continuing the quote -- how 16 do you know if you have increased serotonergic 17 transmission acutely and after repeated dosing in 18 multiple serotonergic pathways that exist in the 19 brain, question mark, end quote. 20 Is that a question you're 21 posing? 22 A. That is indeed a question that 23 I was posing in 1989. 24 Q. All right. Then you go on to Page 215 1 say, one way -- quote, one way would be to 2 measure some event that serotonin affects in the 3 postsynaptic neurons directly. Such an event 4 might be a biochemical change, that is an 5 increase or decrease in a second messenger, like 6 cyclic AMP or -- help me. 7 A. Phosphatidylinositol. 8 Q. Or it might be a change, 9 paren, up or down, close paren, in the firing of 10 those neurons measured electrophysiologically, as 11 two examples. Alternatively, one might measure 12 more globally a functional change resulting from 13 the increased serotonergic signals, such as a 14 change in behavior, in endocrine secretion, in 15 body temperature, in blood pressure, or something 16 else. These things usually can't be done in as 17 straightforward a manner as one would like, 18 period, end quote. 19 Now, if appears to me that you 20 posed possible answers to your questions -- to 21 the questions that you posed in that paragraph, 22 is that correct? 23 A. I provided general answers to 24 the question which was posed, yes. Page 216 1 Q. You said that back in 1989, 2 you didn't know for sure exactly how to answer 3 the question posed, is that right? 4 A. No, I don't think that's what 5 it says. 6 Q. Well, I thought you said today 7 that then you didn't know what the answer was 8 concerning how do you know if you have increased 9 serotonergic transmission acutely and after 10 repeated dosage in the multiple serotonergic 11 pathways that exist in the brain, is that 12 correct? 13 A. You thought I said what? 14 Q. I thought you said that when 15 you wrote this in 1989, that you didn't know the 16 answer to the question posed. 17 A. I don't recall saying that. 18 Q. Is there a way to know if you 19 have increased serotonergic transmission acutely 20 and after repeated dosing in the multiple 21 serotonergic pathways that exist in the brain? 22 A. There are several ways, yes. 23 Q. And are those the ways that 24 you outlined? Page 217 1 A. Those are -- yes, those are 2 some of those ways. 3 Q. Are there now other newer ways 4 or more accepted ways? 5 A. I'm sure there are additional 6 ways. 7 Q. But you don't know what they 8 are right now? 9 A. Well, they would probably fit 10 into the outline that is here. In other words, 11 the next to last sentence in that paragraph says 12 alternatively one might measure more globally a 13 functional change, resulting from the increase 14 serotonergic signals, such as, and it lists 15 several things. And it says or something else. 16 So that something else would probably embrace 17 anything that has been found since then. 18 Q. My question is: Do you recall -- 19 do you know of anything specifically now of 20 something that's been found since August, 1989 to 21 make this measurement? 22 A. Nothing comes immediately to 23 mind, but I can't so quickly sort out in my head 24 what was discovered before 1989 and what was Page 218 1 discovered afterwards. 2 Q. Okay. You say in the last 3 paragraph, Thus, I don't think reviewing receptor 4 changes is the same as reviewing changes in 5 neurotransmission. Can you explain or elaborate 6 on that? 7 A. Yes, referring back to Exhibit 8 3. 9 Q. Three? 10 A. The process of 11 neurotransmission refers to how well -- how 12 rapidly signals are being transmitted along this 13 pathway, and that is a composite of how much 14 serotonin is out here in the synaptic cleft, and 15 how responsive these receptors are to that 16 serotonin. Just talking about the receptors is 17 only part of the story, you've got to know both 18 in order to make any judgment of 19 neurotransmission. There might, in fact, be 20 twenty-five percent fewer receptors, that doesn't 21 mean there's twenty-five percent less 22 neurotransmission, there may well be more 23 neurotransmission with twenty-five percent fewer 24 receptors. Neurotransmission is not the same as Page 219 1 number of receptors. 2 Q. But aren't the receptors and 3 the activity of the receptors the key to 4 neurotransmission? 5 A. The activities of the 6 receptors, meaning the extent to which they were 7 being activated by the neurotransmitter, yes. 8 Q. So in that sense, the 9 receptors are the key to neurotransmission, 10 aren't they? 11 A. This concept is really very 12 simple, it seems to me. The transmission is 13 influenced by the extent of activation of these 14 receptors, which it must be obvious, depends both 15 upon the amount of serotonin that's there and the 16 number of receptors that's there and their 17 function. And to look at one alone and talk 18 about the number of receptors is of course not 19 the same as talking about the total process of 20 neurotransmission. 21 Q. All right. 22 (PLAINTIFFS' EXHIBIT NO. 6 WAS 23 MARKED FOR IDENTIFICATION AND 24 RECEIVED IN EVIDENCE.) Page 220 1 Q. Read for me Exhibit 6. 2 A. (Witness complies.) 3 Q. Have you read it? 4 A. Yes, I have. 5 Q. Do you recall authoring 6 Exhibit 6? 7 A. Yes, I do. 8 Q. Doctor Fuller, what were the 9 circumstances that caused you to write Exhibit 6? 10 A. Well, I would judge it to be a 11 telephone conversation that I had with a Newsweek 12 reporter. 13 Q. And did the Newsweek reporter 14 bring up the subject of down regulation and 15 serotonin production? 16 A. That is what this memo says, 17 yes. 18 Q. Do you recall specifically 19 speaking with the reporter? 20 A. No, other than through the 21 help of this memo, no. 22 Q. Do you recall why you had 23 directed this memo to the individuals mentioned 24 in this group, up on the top left-hand side of Page 221 1 the page under the April 4th date? 2 A. It no doubt has to do with the 3 explanation in the first paragraph that this is a 4 type of misunderstanding that I expected we will 5 hear again, even though I didn't spell hear 6 right, and therefore I was addressing it to those 7 people I thought most likely to hear those 8 things. 9 Q. Do you think that you have 10 adequately summarized what your opinions are in 11 connection with down regulations and the 12 misunderstandings that have been left with 13 respect to down regulations in this memo? 14 A. I would hope it would be 15 adequate, yes. 16 Q. You can't think of anything 17 that you would like to add or delete from this 18 memo at this time, in explaining down regulation 19 and in explaining the misconceptions involved in 20 down regulation? 21 MR. MYERS: Before he answers, let me 22 object to the form to the extent you're trying to 23 direct him to have recite all his opinions with 24 respect to down regulation when he told you he Page 222 1 wrote it in response to a misconception that 2 arose in a discussion with a newspaper reporter 3 in a specific instance. That's not an 4 appropriate question. 5 MR. SMITH: You can't be the judge of 6 what an appropriate question is. 7 MR. MYERS: That's why judges rule on 8 objections, that's what I told you yesterday. At 9 least in most states I've been in. 10 Q. Can you think of anything that 11 you need to add or delete, Doctor Fuller, in 12 connection with the controversy and your 13 explanation over the misunderstanding with 14 respect to down regulation? 15 A. I don't know that there's any 16 controversy over the misunderstanding, so could 17 you rephrase the question? 18 Q. Well, I believe you said 19 earlier that you think this is something that 20 should seem clear and doesn't seem to be 21 something that should be of much scientific 22 debate, is that correct? 23 A. I don't recall making that 24 statement with regard to this memo, no. Page 223 1 Q. Well, with respect to the 2 theories of down regulation that you were 3 explaining earlier in connection with Exhibit 3. 4 A. What I said was that I think 5 the concept is fairly simple, that 6 neurotransmission involves the extent of 7 activation of these receptors, which is 8 determined both by the concentration of serotonin 9 acting on the receptors and by the number of 10 receptors and their functional state. I don't 11 think that's exactly the same as what you were 12 saying. 13 Q. Well, you're trying to provide 14 some clarification, I think you term it in your 15 memo, the last sentence of the first paragraph, 16 thus I am supplying the following clarification. 17 A. Yes, that's -- that refers to 18 a clarification of the use of the term down 19 regulation of serotonin production, which is not 20 a term that I would have ever used, but rather a 21 term that someone else was using. 22 Q. Is down regulation, in the 23 context of serotonin and neurotransmission, a 24 scientific term? Page 224 1 A. The term down regulation, as I 2 have heard it used by neuropharmacologists and 3 psychopharmacologists, in relationship to 4 serotonin neurotransmission, has referred to 5 adaptive changes in receptors for serotonin. And 6 that is not the term that is used here. 7 Q. You're saying that the 8 misunderstanding is people are using down 9 regulation in describing neurotransmission along 10 the neurons in general, and that that shouldn't 11 be used, is that correct? 12 A. No, that is not correct. 13 Q. Okay. Then tell me what is 14 accurate in connection -- 15 A. If you look at Exhibit 6, the 16 third line uses the phrase down regulation of 17 serotonin production. That is the term that I've 18 just said is not one that is used by knowledgable 19 neuropharmacologists. 20 Q. Well, is serotonin production 21 reduced in the presynaptic neuron in the presence 22 of Fluoxetine? 23 A. Yes, I explained that in 24 considerable detail earlier. Page 225 1 Q. All right. But that doesn't 2 have anything to do with the actual transmission 3 of the impulse, is that what you're saying? 4 A. No, that is not what I'm 5 saying. 6 Q. Okay. I just want to be 7 clear, Doctor, and I know it's late and I'm not 8 trying to beat the subject to death, I'm just 9 trying to get it straight. Please bear with me a 10 little longer. 11 A. I don't mind explaining it 12 once again if you would like. 13 Q. Let's try once again. 14 A. When uptake is inhibited and 15 serotonin increases in the synaptic cleft, there 16 is increased activation not only of the 17 postsynaptic receptors, but also of the 18 presynaptic autoreceptors, so that the amount of 19 serotonin that is being made and released is 20 diminished. Those changes occur because of the 21 increased amount of serotonin in the synaptic 22 cleft. So they do not mean that serotonin 23 neurotransmission is decreased, they are 24 occurring because there is more serotonin here in Page 226 1 this synaptic cleft, and therefore there is more 2 activation of the postsynaptic receptors. Those 3 are acute changes that occur within minutes after 4 giving an uptake inhibitor to an animal, let's 5 say, where we can measure these things. So what 6 I'm taking about is based on studies in animals, 7 essentially. 8 Over time, with repeated 9 administration of an uptake inhibitor, this 10 increased amount of serotonin in the synaptic 11 cleft can lead to a second type of adaptive 12 response which is a down regulation of receptors. 13 And that can occur apparently both with some, but 14 not all, postsynaptic receptors, and some 15 presynaptic receptors. Through all of this, so 16 far as we can tell, serotonin neurotransmission 17 is increased after uptake inhibition. It's not 18 increased as much as it would have been if those 19 adaptive changes had not occurred, but they are 20 occurring because there is more serotonin there 21 in the synaptic cleft, so there is more 22 neurotransmission. And that, in essence, is the 23 situation as I understand it. 24 * * * * * * * * * * Page 227 1 CROSS EXAMINATION 2 BY MS. ZETTLER: 3 Q. What if the receptor, the one 4 on your diagram in the postsynaptic cleft, is the 5 one that's down regulated, isn't that going to 6 interrupt neurotransmission? 7 A. No. Interrupt meaning to 8 stop, no. 9 Q. How does that affect 10 neurotransmission, if at all? 11 A. It would limit the extent of 12 the increase of neurotransmission. If there is 13 more serotonin out in the synaptic cleft and it's 14 activating the receptor to a greater extent, and 15 increasing the neurotransmission, then the 16 decrease in the receptor number or function, 17 either one, if it occurs, would limit the extent 18 of that increase. 19 Q. What if all the receptors on 20 that particular postsynaptic neuron were down 21 regulated as a result of being over activated? 22 A. What if all the receptors were 23 down regulated? 24 Q. Right. Page 228 1 A. I don't know what you mean by 2 that. 3 Q. You said earlier that the 4 neurons have more than one type of receptor, they 5 have multiple receptors, correct? 6 A. Right. 7 Q. What if all the receptors on a 8 particular postsynaptic neuron were down 9 regulated, how would that affect 10 neurotransmission? 11 A. Then all the 12 neurotransmissions regulated by any of those 13 receptors would be increased less than it would 14 have been if it were not down regulated. 15 Q. So you're saying -- what's the 16 effect of down regulation? 17 A. It's to limit the increase in 18 neurotransmission. 19 Q. Is there ever a point where 20 down regulation renders a receptor unable to be 21 activated? 22 A. Well, as I explained earlier, 23 there are at least two different types of down 24 regulation that can occur, one is a reduction in Page 229 1 receptor number, and the other would be a 2 reduction in receptor efficiency. So far as I 3 know, and can remember, all of the decreases in 4 serotonin receptors that have been reported, and 5 let me emphasize that it's probably only 6 serotonin receptors labeled with tritiated 7 serotonin that have been shown to undergo this 8 kind of down regulation. So far as I know, that 9 has been a decrease in receptor number, I don't 10 recall any example of where there was a decrease 11 in receptor sensitivity or efficacy. So that 12 obviously those receptors that are not there 13 anymore will not be active, but those receptors 14 that are still there will be as active as they 15 were before. And since there is an increased 16 amount of serotonin out here, the overall result 17 is an increase in the amount of 18 neurotransmission, but a somewhat small increase 19 than would have occurred if those receptors 20 hadn't been down regulated. 21 Q. What if you removed the 22 Fluoxetine and they're down regulated, either 23 gone completely or functionally less? 24 A. Then the answer would come Page 230 1 back to normal. 2 Q. Do you know that for a fact? 3 A. Do I know that for a fact, as 4 well as I know the other things for a fact. 5 Q. Have there been tests that 6 have shown that the down regulation or the 7 function of the receptors that are still there 8 goes back to normal? 9 A. You mean that the changes in 10 receptors have been shown don't last forever? 11 Q. Right. 12 A. I think that's been shown. 13 I'm not aware of any example, in all of 14 pharmacology, where adaptive changes in receptors 15 like that have been shown to persist longer than 16 the stimulus that caused them. 17 Q. What about the ones that are 18 no longer there? 19 A. Again -- 20 Q. You said earlier -- you 21 implied that they -- 22 A. It's a dynamic thing. Every 23 receptor that's there wasn't there some time 24 back, and won't be there sometime in the future. Page 231 1 There's a dynamic -- I can's say it, so I won't 2 use it, but there's a dynamic nature to these 3 receptors, they're always undergoing turnover. 4 Q. Okay. How long does it take 5 to turn over? 6 A. I don't know the answer to 7 that, I don't know that that's been determined 8 with these serotonin receptors. 9 Q. Has anybody tried to determine 10 that? 11 A. Probably, but not that I 12 specifically remember. 13 Q. Do you know if anybody has 14 tried and failed? 15 A. No, I simply don't remember. 16 Q. Have you tried to determine 17 that? 18 A. No. 19 Q. Why not? 20 A. Well, I don't -- that's not 21 the type of experiments that I do, I don't do 22 radiologic receptors which would be one way of 23 trying to approach that. It is not to my mind -- 24 it's not a question that would help me in my Page 232 1 research particularly. 2 Q. It's not important to your 3 research to try to determine how long a destroyed 4 receptor would take to regenerate? 5 MR. MYERS: I object to the form. He 6 never said it was destroyed. 7 Q. It's no longer there, correct, 8 some of them are no longer there, right, and they 9 regenerate? 10 MR. MYERS: Objection. 11 A. No, I think you misunderstand -- 12 MR. BRENNER: I think you 13 misunderstood. 14 MR. SMITH: We're going to have to get 15 one lead counsel here. 16 MR. MYERS: So are you -- 17 MR. BRENNER: As long as you two are 18 asking questions, we will interject objections, 19 particularly when you're abusing the witness. 20 MR. SMITH: I'm abusing the witness, 21 I'm not even talking to the witness, how can I be 22 abusing the witness? 23 MR. BRENNER: Your co-counsel is. 24 MS. ZETTLER: Do you feel abused, Page 233 1 Doctor? 2 MR. MYERS: Don't answer that, Doctor 3 Fuller. 4 MS. ZETTLER: I apologize. 5 MR. MYERS: Have you turned the 6 examination over to her now? 7 MR. SMITH: I think she grabbed it 8 away from me. 9 MR. MYERS: What is the question, 10 then? 11 MS. ZETTLER: Can you read it back? 12 (THE COURT REPORTER READ BACK THE 13 REQUESTED TESTIMONY.) 14 Q. So it's not a circumstance 15 where some of the receptors are, in effect, not 16 able to activate anymore after awhile in down 17 regulation? 18 MR. MYERS: Object to the form. 19 Q. I thought there were two 20 categories you talked about, some whose ability 21 to be activated were decreased, and some that no 22 longer worked at all, correct? 23 A. I explained it in a general 24 sense as the two kinds of adaptive changes that Page 234 1 can occur with receptors in general. 2 Q. What were those two kinds 3 again? Let's get this straight. 4 A. One would be where there's an 5 actual change in the number of receptors, either 6 an increase or a decrease. The second is when 7 the number of receptors remains the same, but 8 their efficiency of transducing messages is 9 altered. 10 Q. Okay. In a down regulation, 11 the number may be decreased, right? 12 A. Some people use the term down 13 regulation to encompass changes in either of 14 those parameters, either a reduction in the 15 number of receptors or a reduction in the 16 efficiency of their transduction of neuro 17 signals. 18 Q. Let's talk about a situation 19 where the number of receptors decreases, okay? 20 A. Yes. 21 Q. So if you're talking about 22 down regulation, that's when you're talking about 23 the possibility of the number of receptors 24 decreasing, correct? Page 235 1 MR. MYERS: I object to the form, 2 that's a possibility. 3 Q. Right. I'm limiting it to the 4 one circumstance where the number decreases, I'm 5 not talking about the level of functioning 6 decreasing, okay. I'm just trying to get it 7 clear what you mean when you say the actual 8 number of receptors decrease. Are you talking 9 about, for instance, as an analogy, ten receptors 10 on a neuron, and then all of a sudden there's 11 only six as a result of down regulation? 12 A. A decrease in the number of 13 receptors, what I mean is that there are fewer 14 receptors at the site as a result of some 15 treatment than there had been before that 16 treatment. 17 Q. Okay. So some of the 18 receptors go away as a result of the treatment, 19 in that circumstance? 20 A. That's not the equivalent to 21 what I said, no. 22 Q. Where am I getting it wrong, 23 Doctor? 24 A. There are two -- at least two Page 236 1 general ways in which the number of receptors 2 could go down. 3 Q. Okay. 4 A. One is that receptors are 5 disappearing at a faster rate than they had been 6 disappearing, and the second is receptors are 7 being made at a slower rate than they had been 8 being made. 9 Q. So as a result of down 10 regulation or down regulation adaptive change, in 11 this instance, where there are less receptors, it 12 can either be because they are disappearing at a 13 faster rate or being made at a slower rate. 14 A. Yes. 15 Q. That's part of the 16 regeneration thing you were talking about 17 earlier, where it's taken into the membrane, I 18 think it was, and it was regenerated within the 19 membrane? 20 A. To the best of my 21 recollection, I have not used the term 22 regeneration in describing this process. The 23 receptor -- what I explained is that there is the 24 dynamic state to these receptors in the membrane, Page 237 1 they are being formed and they are being 2 degraded. And it is not a matter of one receptor 3 being regenerated, it is a matter of new 4 receptors being made, and old receptors being 5 degraded. 6 Q. Degraded, is that what you 7 said? 8 A. Yes. 9 Q. Degraded at a quicker rate 10 than they would have been without the adaptive 11 change? 12 A. Well, in the case -- in the 13 case of a decrease in the number of receptors, 14 again, that could occur hypothetically by an 15 increased rate of receptors being degraded or 16 reduced rate of receptors being made. 17 Q. Are all receptors subject to 18 this dynamic that you're talking about? 19 A. Yes, as part of it. 20 Q. That's been proven in tests, 21 has somebody tested for that, regeneration on all 22 receptors? 23 MR. MYERS: Object to the form, you 24 again use that term regeneration. Page 238 1 Q. I'm sorry, this dynamic. Did 2 somebody test it to see if this dynamic applies 3 to all receptors? 4 A. This dynamic nature applies 5 essentially to all of biology, not just 6 receptors, but other constituents of the cell 7 membrane or the cell itself, enzymes, 8 transporters, et cetera. If you're asking 9 whether there is experimental data with each and 10 every serotonin receptor that we now know about, 11 the answer certainly is no, because some of those 12 receptors have only been discovered quite 13 recently, and there would not be methodology 14 available for someone to do that. But if you're 15 asking whether biologists would expect that this 16 is occurring, then the answer is yes, I think 17 every biologist would expect that is occurring. 18 Q. The problem that you have with 19 the discussion you had with the reporter for 20 Newsweek -- the discussion you had with the 21 reporter from Newsweek is that it's not so much 22 whether or not the receptors have been affected 23 by down regulation, it's that you can show that 24 the transmission is still occurring, correct, the Page 239 1 neurotransmission is still occurring? 2 A. The problem is more general 3 than that. The problem, to me, is that there is 4 an apparent confusion of two different kinds of 5 adaptive responses, and an apparent 6 misunderstanding of why those have occurred and 7 what they mean. 8 Q. They're confusing turnover -- 9 or combining turnover and down regulation to some 10 extent, correct? 11 A. That's correct. 12 Q. But as far as the impact or 13 alleged impact that Fluoxetine has -- an indirect 14 impact that Fluoxetine has on the receptors in 15 the form of down regulation, that doesn't concern 16 you so much because you can still show that the 17 neurotransmission is taking place, correct, in 18 fact increases according to your testimony? 19 A. I don't remember saying that. 20 Q. Okay. Which part don't -- I 21 mean is the down regulation affecting 22 neurotransmission as far as you can tell in 23 animals that are administered Fluoxetine? 24 A. I can tell you what I would Page 240 1 expect, may we do that? 2 Q. Sure. 3 A. What I would expect is exactly 4 as I said earlier, I think, that as a result of 5 the increased amount of serotonin that is in the 6 synaptic cleft, there are at least two different 7 kinds of adaptive changes that have been shown to 8 occur. The most rapid one is a reduction in the 9 rate at which serotonin is being made and 10 released, and that limits the extent to which 11 serotonin increases here. 12 Q. That's called turnover? 13 A. That could be called -- 14 Q. Decreased turnover? 15 A. That could be called decreased 16 turnover, yes. I think it's more informative to 17 say a decreased in the amount of serotonin that 18 has been made and released, but if you would 19 prefer turnover, I would allow you to use that. 20 There's been a later adaptive change in certain 21 serotonin receptors, and apparently not all of 22 them, which again limits the extent to which 23 neurotransmission is increased. There is no 24 hypothetical basis that I can think of, and no Page 241 1 experimental data that I know of, that would 2 suggest neurotransmission is not increased during 3 all of this, but rather these adaptive changes 4 place limits to the extent to which that increase 5 occurs. 6 Q. I guess my question then is 7 how do you know that neurotransmission increases? 8 A. By virtue of many of the 9 measurements that were referred to in earlier 10 memos, and that I have referred to in numerous 11 publications, such as Exhibit 4, the section 12 seven entitled Functional Effects of Fluoxetine 13 In Vivo, and section eight, entitled Therapeutic 14 Effects of Fluoxetine in Humans. 15 Q. Repeat those again, Doctor, I 16 didn't have a copy. 17 MR. SMITH: Didn't you say section 18 seven and eight? 19 THE WITNESS: Yes. 20 Q. One of those effects is 21 Fluoxetine reducing rapid eye movement sleep in 22 rats and cats? 23 A. Yes. 24 Q. There are a number of Page 242 1 serotonin neuron subtypes, correct? 2 A. I don't know what you mean by 3 that. 4 Q. I'm sorry, serotonin receptor -- 5 A. Serotonin receptor subtypes, 6 yes. 7 Q. In fact, I think Doctor Wong 8 told us yesterday there were from fifteen to 9 seventeen that had been at least speculatively 10 identified, some have been identified and some 11 they are still arguing over whether or not they -- 12 A. Yes, the exact number would 13 depend on how rigid you are in the criteria, but 14 that is -- the essence of that is correct. 15 Q. Out of those seventeen, how 16 many have a known function at this point? 17 A. The extent to which the 18 function of each of those is known varies, 19 there's a spectrum, so I couldn't answer your 20 question by saying X number are known and Y is 21 unknown. I would say there's different amounts 22 known about each of those. For example some of 23 those have been only recently cloned, and not 24 even previously known to exist, so there's Page 243 1 virtually nothing known about their function. 2 Whereas some of the others, we have available 3 drugs that interact with them selectively, so 4 more is known about their function. 5 Q. Which serotonin subtype -- 6 receptor subtypes have been linked to rapid eye 7 movement sleep in rats? 8 A. I'm not aware that that 9 specific issue has really been investigated 10 because the studies on rapid eye movement sleep, 11 for example that are referred to here, were 12 published in 1978, at which time very little was 13 known about serotonin receptor heterogeneity, 14 certainly most of the current known receptor 15 subtypes were not known then. There has been 16 some more recent work on rapid eye movement 17 sleep, but whether anyone has specifically tried 18 to sort out what receptor subtypes are involved 19 in that, I don't remember offhand. 20 Q. Okay. How is it that you know 21 that Fluoxetine reduces rapid eye movement sleep 22 in rats then? 23 A. How is it that I know that? 24 Q. Right. Because they simply Page 244 1 gave it to the rats and their REM sleep was 2 reduced? 3 A. Yes, yes. 4 Q. Other than that, there was no 5 determination made on how -- from the initiating 6 the dosage of Fluoxetine to the reduction in REM 7 sleep other than the fact that there was a 8 correlation between giving, the time correlation 9 between giving the Fluoxetine and the reduction 10 in REM sleep, right? 11 MR. MYERS: Let me object to the form 12 only to the extent you may be assuming there were 13 no controls or things like that, and I don't know 14 if there were, but if your question says it -- 15 Q. Can you answer my question, 16 Doctor? 17 A. No, I didn't understand what 18 you -- 19 Q. I just want to know if other 20 than the fact that it was noted that in rats, 21 once Fluoxetine was administered their REM sleep 22 decreased. Other than that fact, was there 23 anything else that was done to determine whether 24 or not Fluoxetine did cause that effect of Page 245 1 reduced REM sleep? 2 A. Are you asking whether or not 3 it caused that effect by influencing serotonin? 4 Q. No, I'm just asking -- in here 5 it says Fluoxetine reduces rapid eye movement 6 sleep in rats and cats. 7 A. Yes. Rats and cats that 8 received identical injections with a vehicle that 9 didn't contain Fluoxetine didn't show that 10 effect, therefore it must have been caused by 11 Fluoxetine. 12 Q. Okay. And as far as how the 13 Fluoxetine actually does reduce the REM sleep, we 14 don't know, other than assuming that it has 15 something to do with inhibiting the uptake of 16 serotonin? 17 A. It's more than that 18 assumption, it's the knowledge that it acts 19 synergistically with the precurser to serotonin 20 5-hydroxytryptophan and the knowledge that other 21 drugs that increase serotonin function also 22 produce the same effect. 23 Q. But you don't know how the 24 neuron in neurotransmission -- serotonin Page 246 1 neurotransmission is affected, and how that 2 effect reduces the REM sleep, in other words you 3 can't sit there and look at a neuron and watch a 4 neuron act, can you? 5 MR. MYERS: Let me object to the form, 6 you asked him two questions. 7 Q. When you sit there, can you 8 watch a neuron in action, can you watch an actual 9 neurotransmission as it occurs, I mean a specific 10 neurotransmission on a specific neuron? 11 A. Can you watch it occurring? 12 Q. Can you actually see it with 13 the naked eye or with a microscope? 14 A. You cannot see a neuron with 15 the naked eye. 16 Q. Can you see it with a 17 microscope? 18 A. Yes. 19 Q. Okay. Have you ever watched a 20 neurotransmission of a serotonin neuron after 21 it's been administered Fluoxetine or Fluoxetine -- 22 A. Through a microscope? 23 Q. Right. 24 A. No. Page 247 1 Q. Why not? 2 A. It isn't possible to do that 3 through a microscope. You can see neurons 4 through a microscope, but you can't see neurons 5 in the intact brain of a living animal through a 6 microscope. 7 Q. Okay. Can you see neurons in 8 the intact brain of a living human through that 9 microscope? 10 A. No. 11 Q. So you really don't know how 12 it all works, right, you're just kind of guessing 13 from what you've seen as far as different 14 chemicals and reactions and things like that? 15 MR. MYERS: I object to the form, you 16 mischaracterized everything he said since about 17 9:00 o'clock this morning. 18 Q. Isn't this really what is 19 called a putitive drug? 20 A. A putitive drug? 21 Q. Right, putitive theory. 22 A. I think it's a real drug. 23 Q. Okay. Is its effects on 24 depression putitive? Page 248 1 A. I think they're real effects, 2 they have been observed by many people. 3 Q. Has it been observed by people 4 at Eli Lilly? 5 MR. MYERS: Objection to the form. 6 MS. ZETTLER: I'm asking him a 7 legitimate question. 8 MR. BRENNER: That is not a legitimate 9 question, even in Texas, I bet. 10 MS. ZETTLER: I'm sure it is in New 11 Jersey. 12 MR. MYERS: What is the question? 13 MS. ZETTLER: Read back the question. 14 (THE COURT REPORTER READ BACK THE 15 REQUESTED TESTIMONY.) 16 Q. The real effects of Fluoxetine 17 in treating depression have been observed by 18 people at Eli Lilly, that's my question. 19 MR. MYERS: I object to the form 20 because it assumes it hasn't been observed by 21 anybody else. 22 MS. ZETTLER: Larry -- 23 MR. MYERS: I'm objecting to the form 24 of the question. Page 249 1 MS. ZETTLER: Well, first of all, I 2 don't think -- it's just a question, okay. 3 MR. MYERS: I object to the form, 4 that's all. 5 MS. ZETTLER: Fine. 6 Q. Have people -- have Eli Lilly 7 employees observed these real effects of 8 Fluoxetine on depression? 9 A. I would assume some of them 10 have. 11 Q. Okay. And people outside of 12 Eli Lilly have allegedly observed these real 13 effects of Fluoxetine on depression, correct? 14 A. Yes, many people outside of 15 Eli Lilly have. 16 Q. And at least some of them have 17 observed the real effects of Fluoxetine on 18 depression during clinical trials, right? 19 A. Yes. 20 Q. And allegedly some of them 21 have observed these real effects on depression in 22 treating their own patients, correct, some 23 doctors? 24 A. Yes. Page 250 1 Q. Some people have also observed 2 adverse events or adverse effects of Fluoxetine 3 on people, have they not? 4 A. I think so. 5 MS. ZETTLER: It's 5:00 o'clock. 6 MR. MYERS: A good breaking point. 7 (DISCUSSION OFF THE RECORD.) 8 MS. ZETTLER: No further questions. 9 * * * * * * * * * * 10 (THE DEPOSITION WAS ADJOURNED AND RESUMED 11 THE FOLLOWING DAY, AS FOLLOWS:) 12 13 14 REDIRECT EXAMINATION 15 BY MR. SMITH: 16 Q. Doctor Fuller, I'm going to 17 ask for your assistance in somewhat of a 18 housekeeping matter. The attorneys from Eli 19 Lilly and Company having in response to an order 20 of the court provided us with a privileged log in 21 connection with documents that they're 22 identifying that have legal protection under 23 federal law. But, I need to get from you some 24 idea, some of the -- maybe a little better Page 251 1 description and maybe a description of some of 2 the people involved. You may not know any of 3 this, you may know some of it, you may be of some 4 help. This will be a nice, easy thing for me to 5 ask you. 6 Do you know a R. A. Conrad at 7 Eli Lilly and Company? 8 A. Yes. 9 Q. Who is R. A. Conrad? 10 A. He is an attorney. 11 Q. All right. 12 Q. Do you recall writing Mister 13 Conrad, and I don't have a date, an E-mail 14 message on R Fluoxetine and R Norfluoxetine? 15 A. I don't specifically recall 16 that, no. 17 Q. But, Conrad is an attorney? 18 A. Yes. 19 Q. Have you ever seen a DEN 20 report? 21 A. A what? 22 Q. DEN, D-E-N. I believe that's 23 an abbreviation for a Drug Experience Network or 24 Drug Epidemiology Network. Page 252 1 A. I don't recall that I've seen 2 one, I'm not sure I know what one would look 3 like. 4 Q. Are you familiar with the term 5 DEN, as it's used in the epidemiology section? 6 A. No, I'm not really familiar 7 with it. 8 Q. Do you know who D. L. Telman 9 is? 10 A. I'm not sure that I do, no. 11 Q. That name doesn't ring a bell 12 with you? 13 A. I know someone named Telman, I 14 don't recognize if those are his initials. 15 Q. Do you know what division 16 Telman is? 17 A. I believe, he's in the legal 18 division. 19 Q. Are you sure about that? 20 A. No, I'm not. 21 Q. Can you tell us for certain 22 that there is a Telman who is an attorney working 23 for Eli Lilly and Company? 24 A. I cannot be certain about Page 253 1 that. 2 Q. Do you recall a document in 3 December, 1984, that was a memo concerning 4 Analgesic Research Committee on Fluoxetine? 5 A. In 1984? 6 Q. Yes. 7 A. No, I don't remember that. 8 Q. Are you familiar with an 9 Analgesic Research Committee on Fluoxetine? 10 A. So far as I know, there is no 11 Analgesic Research Committee on Fluoxetine. 12 Q. Well, was there in 1984? 13 A. Not so far as I know. 14 Q. You've never heard of an 15 Analgesic Research Committee on Fluoxetine, is 16 that correct? 17 A. That is correct. 18 Q. In 1984, were you the project 19 team leader for Fluoxetine? 20 A. 1984, I think I ceased to be 21 project team leader sometime before 1984. 22 Q. Did you continue to be on the 23 Fluoxetine project team? 24 A. Yes, I did. Page 254 1 Q. After 1984? 2 A. Yes, I did. 3 Q. And were you on the team in 4 1984? 5 A. Yes, I was. 6 Q. What was your function on the 7 Fluoxetine project team in December of 1984? 8 A. I was a member -- I was a 9 member representing pharmacology. 10 Q. Who was the chairman of the 11 team in 1984? 12 A. As I mentioned, I don't 13 remember the specific date that I stopped being 14 chairman of the project team, but when I stopped 15 being chairman, David Brennan became chairman. 16 Q. Who is C. W. Ashbrook? 17 A. He is an attorney. 18 Q. Who is B. Wood? 19 MR. MYERS: B? 20 MR. SMITH: B, as in boy. 21 A. I don't recognize that name. 22 Q. Who is S. R. Twiss, T-W-I-S-S? 23 A. I don't believe I know that 24 individual. Page 255 1 Q. Who is R. Acosta? 2 A. I'm sorry, would you spell it? 3 Q. A-C-O-S-T-A, initial 4 R. Acosta. 5 A. I believe that's someone who 6 was in the marketing component. 7 Q. Do you recall receiving a memo 8 in September of 1988, from -- or did you direct a 9 memo to Mister Acosta in September of 1988, 10 concerning Desyrel and Prozac comparative -- 11 which was a comparative promotional piece? 12 A. It's certainly possible I did 13 so, but I could not verify that from memory. 14 Q. But, you don't recall that 15 Acosta's an attorney, your recollection is that 16 Acosta is someone in marketing? 17 A. I remember one individual 18 named Acosta who was in marketing. Whether that 19 is this individual, I don't know for sure. 20 Q. Well, the document indicates 21 that you issued a memo to this individual, this 22 Acosta individual, in September of 1988. Do you 23 think more than likely that's the individual in 24 marketing? Page 256 1 A. That's the only individual 2 with that name that I am able to think of right 3 now. 4 Q. And do you recall writing a 5 Desyrel-Prozac comparative promotional piece? 6 A. I'm sorry, would you repeat 7 that? 8 Q. Do you recall writing a 9 Desyrel-Prozac comparative promotional piece or 10 supplying input for such a promotional piece? 11 A. I'm not involved in writing -- 12 I'm not sure I know what you mean by promotional 13 pieces, but I don't think I would be involved in 14 writing them. 15 Q. Well, this is something that's 16 been prepared by the Lilly lawyers, Doctor 17 Fuller, and that's the way they're referring to 18 it. 19 A. The reference here is to a 20 memo concerning such a promotional piece. 21 Q. Yes. 22 A. I would not have written the 23 promotional piece, I might have written a memo 24 concerning -- Page 257 1 Q. That's why I asked, did you 2 provide some input for a promotional piece by 3 virtue of a memo. Do you have any recollection 4 of that? 5 A. No, I don't have any detailed 6 recollection of that. I'm familiar with the drug 7 Trazodone and it's quite possible I supplied some 8 information about how it compares to Fluoxetine. 9 But, in specific regard to a promotional piece, 10 I'm not even sure I understand what you mean -- 11 what is meant by a promotional piece. 12 Q. You understand that's not my 13 term, that's the term that was designated on this 14 log, by the log provided to us by the Lilly 15 lawyers, you understand that? 16 A. Yes, I do. 17 Q. You are not an attorney. 18 A. That is correct. 19 Q. You've not had any education 20 or training in legal matters. 21 A. That is correct. 22 Q. Who is J. A. Webber, do you 23 know, W-E-B-B-E-R? 24 A. I believe that is someone in Page 258 1 the regulatory division. 2 Q. And Dan Masica? 3 A. He is a physician at Lilly. 4 Q. Neither J. A. Webber nor 5 Doctor Dan Masica are attorneys, as far as you 6 know? 7 A. As far as I know, they are 8 not. 9 Q. Do you know an individual at 10 Lilly called by the name of S. Zordan, 11 Z-O-R-D-A-N? 12 A. I don't think I do, no. 13 Q. I believe you said an 14 individual by the name of S. R. Twiss you think 15 is in the legal department? 16 A. No, I said I don't recognize 17 that name at all. 18 Q. Do you recall seeking any 19 advice of a legal nature from anyone within the 20 legal department at Eli Lilly and Company 21 concerning your research with respect to 22 Fluoxetine? 23 MR. MYERS: At what point in time. 24 MR. SMITH: At any time, that you were Page 259 1 involved in Fluoxetine research. 2 A. No, I don't. 3 Q. You never felt the need to 4 seek legal counsel in connection with any of the 5 work you were doing at Lilly with respect to 6 Prozac? 7 A. No, I didn't. 8 Q. Do you know anybody at Lilly 9 by the name of M. Abbott, A-B-B-O-T-T? 10 A. I don't recognize that name. 11 Q. In your studies in connection 12 with Fluoxetine and the down regulation of 13 certain postsynaptic receptors, did you ever do 14 any studies to determine how long particular 15 receptor sites were down regulated, how long -- 16 do you understand what I'm asking you? 17 A. I don't think I've indicated 18 that I have ever done any studies personally 19 related to down regulation of receptors in 20 response to Fluoxetine. To the best of my 21 recollection, I have probably done one experiment 22 which would pertain to that particular subject 23 and it did not indicate that the receptors 24 involved in the effect I was studying were down Page 260 1 regulated. 2 Q. Okay. The one study that you 3 conducted where that information was available or 4 could potentially come up, you found that -- or 5 you didn't see any evidence of down regulation? 6 A. That's correct. 7 Q. But, as I understand it, 8 studies done by Doctor Wong and others at Lilly, 9 indicated that there was a down regulation of 10 these receptors? 11 A. Not of the receptors that were 12 involved in the effect I was studying -- other 13 receptors. 14 Q. No, I'm talking about other 15 receptors, serotonin receptors, correct? 16 A. Other serotonin receptors. 17 Q. And those would have been 18 located where, those other serotonin receptors? 19 A. I don't specifically remember 20 the area of the brain that was studied in Doctor 21 Wong's experiments, that would be described in 22 his publications. 23 Q. Do you know of any study done 24 by anyone, at any time, that indicates how long Page 261 1 these serotonin receptors remain in a down 2 regulated state? 3 MR. MYERS: At Lilly or elsewhere? 4 MR. SMITH: Either. 5 A. I have read probably most of 6 the publications on that subject, but, which of 7 those studies actually investigated how long the 8 effect occurred, I could not tell you from 9 memory. 10 Q. Are there any studies that 11 examine how long the effect of down regulation 12 occurred? 13 A. I think it must be apparent 14 from my previous answer that I couldn't tell you 15 that from memory. 16 Q. Well, it wasn't to me. So, 17 you don't know -- so we'll make sure the record 18 is straight, Doctor Fuller, you don't know 19 whether or not there have been any studies to 20 determine how long those receptors that are down 21 regulated remain in a down regulated state, is 22 that correct? 23 A. As I mentioned, if this is 24 described in the publications that I have read Page 262 1 then I certainly knew that at one time, but I do 2 not remember it at this moment. 3 Q. Well, are you saying you think 4 there are some studies that address that issue? 5 A. I'm saying there are some 6 studies which may address that issue, in which I 7 don't remember in sufficient detail at the moment 8 to tell you whether they do or don't address that 9 particular issue. 10 Q. Well, do you know of any 11 studies where research animals, i.e. rodents, 12 rats or mice, were administered Fluoxetine, then 13 for a period of time -- then the Fluoxetine was 14 discontinued, then after a period of time the 15 rats were sacrificed or the experimental animal, 16 whatever, was sacrificed, and there was some 17 study to determine whether or not there was any 18 evidence of any injury or long-term effects of 19 the down regulation which had occurred in the 20 receptors of that particular research animal? 21 A. I think the studies we have 22 been talking about are the studies of the general 23 type that you described, where Fluoxetine is 24 given to a test animal for a period of time and Page 263 1 then discontinued. And in some such studies, 2 there have been an examination of receptors for 3 serotonin labeled with some appropriate 4 radioligand that have suggested there is a down 5 regulation of those receptors, that is a reduced 6 number of certain receptors, and in some studies 7 there has been the finding that there is no down 8 regulation of those receptors. And in those 9 studies, where there was a down regulation of 10 receptors, to my knowledge, there would never be 11 any expectation that that would result in injury 12 and no evidence of any sort that there was any 13 injurious consequence of that adaptive change. 14 Q. Was there any study done to 15 specifically determine that, whether or not there 16 was any injurious changes by virtue of this down 17 regulation is my question. 18 MR. MYERS: Where that was the study 19 objective or a study objective? 20 A. Perhaps, I need to understand 21 what you mean by injurious. 22 Q. That's the term that you used 23 and so you can define it in any way you would 24 like. Page 264 1 MR. MYERS: Let me object to the form. 2 You used the word injured, though, in the 3 question that preceded it, you laid the injury as 4 the predicate in your question. 5 MR. SMITH: He gave the response that 6 there was no injurious expectations that would be 7 found. 8 Q. What did you mean, Doctor 9 Fuller, when you used the term injurious with 10 respect to the expectations that might be found 11 following this down regulation condition? 12 A. I was repeating the term that 13 you had used in the question. To me the term 14 injurious would mean some sort of deleterious 15 consequence, some consequence which would be a 16 disadvantage to the animal. I don't think people 17 who study down regulation of receptors would 18 consider that such a type of adaptation. It 19 would generally be an adaptation that would be 20 expected to be beneficial to the animal. So, I 21 don't know what kind of effects you might be 22 thinking about, when you ask whether anyone has 23 looked specifically for injurious changes. 24 Q. Well, has anyone done a study Page 265 1 to determine how long this down regulation of 2 these receptor sites continues? 3 MR. MYERS: I object to the form, I 4 think he answered that about three or four 5 questions ago. Doctor Fuller, answer Mister 6 Smith's question again. 7 A. The answer, which I gave 8 earlier, is that there have been some published 9 studies on the matter of whether adaptive changes 10 in receptors occur in animals after repeated 11 administration of Fluoxetine, and in some such 12 studies there were changes found in receptors, 13 serotonin receptors, and in some studies there 14 were not. In those studies in which there were 15 changes found, I do not recall, without referring 16 to those papers, whether the duration of those 17 changes was measured. 18 Q. As we sit here today, would 19 that hold any interest -- would that be of any 20 interest to you in connection with your work on 21 Fluoxetine? 22 A. In connection with my work on 23 Fluoxetine, I don't see that that would be of any 24 value to know that. Page 266 1 Q. Why would it not be of any 2 value? 3 A. Because none of the research 4 that I have done on Fluoxetine has concerned the 5 down regulation of receptors at all, except for a 6 limited study which I mentioned earlier where the 7 phenomenon that we were measuring indicated that 8 there was no adaptive changes after repeated 9 administration of Fluoxetine in those receptors 10 which mediated those effects. 11 Q. Why was the Fluoxetine project 12 team originated? 13 A. For the purpose of developing 14 Fluoxetine as a drug candidate. 15 Q. Did the Fluoxetine team -- 16 Fluoxetine team oversee or review the various 17 phases the research on Fluoxetine went through 18 from its beginning stages up until time -- the 19 time that Fluoxetine was approved by the Food and 20 Drug Administration for sale to the public in the 21 United States of America? 22 A. Yes. 23 Q. And was it the purpose of the 24 Fluoxetine team to review the state of the Page 267 1 research and the state of the studies on a 2 periodic basis? 3 A. That was one of the purposes, 4 yes. 5 Q. And was it another purpose of 6 the team to give further instructions or 7 directions concerning further things to be done 8 in connection with the research and clinical 9 trials in connection with Fluoxetine? 10 A. It was certainly to plan for 11 those things which needed to be done, yes, if 12 that's what you mean. 13 Q. And you all were meeting on a 14 regular basis throughout the time of the 15 preclinical and clinical trials? 16 A. We met periodically during 17 that time. 18 Q. Do you know whether or not the 19 Fluoxetine team meetings' minutes were sent to 20 the Food and Drug Administration? 21 A. The minutes of the Fluoxetine 22 project team, was that the question? 23 Q. Yes. 24 A. No, I do not know. Page 268 1 Q. Do you recall there coming a 2 period of time, Doctor Fuller, that the clinical 3 trials in Fluoxetine were going to be 4 discontinued in '78-79? 5 A. No, I don't remember that. 6 Q. Do you remember a situation 7 where Doctor Shulman, you recall who Doctor 8 Shulman was? 9 A. Yes, I do. 10 Q. Doctor Shulman was at one time 11 the medical monitor in connection with the 12 Fluoxetine clinical trials in humans, wasn't he? 13 A. Yes, he was. 14 Q. And do you recall that Doctor 15 Shulman had made a recommendation that the 16 Fluoxetine clinical trials be discontinued 17 because the clinical trials, up to that point, 18 had not established any efficacy on the part of 19 Fluoxetine in treatment of depression? 20 A. No, I don't remember that. 21 Q. Are you saying it didn't occur 22 or are you saying you don't recall that? 23 A. To the best of my 24 recollection, it didn't occur. Page 269 1 Q. Well, do you recall that 2 Doctor Shulman was replaced as the medical 3 monitor for the Fluoxetine clinical trials by 4 Doctor I. H. Slater? 5 A. I think Doctor Shulman left 6 the company. At some later stage, Doctor 7 I. H. Slater became the medical monitor. 8 Q. Well, don't you remember, 9 Doctor Fuller, that Doctor Slater became the 10 medical monitor immediately after Doctor Shulman? 11 A. I don't remember if that was 12 true or not. 13 Q. Were you the project -- were 14 you the Fluoxetine project team leader in '78 and 15 '79? 16 A. Yes. 17 Q. Well, if Doctor Slater hadn't 18 been the medical monitor immediately after Doctor 19 Shulman, who would it have been, Doctor Fuller? 20 A. I don't remember the sequence 21 of events that long ago. I think there may not 22 have been a medical monitor in the interim, but I 23 don't remember that Doctor Slater was necessarily 24 appointed medical monitor the day Doctor Shulman Page 270 1 left. 2 Q. Within a reasonable time, I'm 3 not talking about an instant passing of the gavel 4 or the stethoscope. I'm talking about being next 5 in line, after a reasonable period of time after 6 Doctor Shulman left, where there wasn't another 7 medical monitor in between Doctor Shulman and 8 Doctor Slater. 9 A. There may not have been 10 another one in between those two, I don't 11 remember that specifically. 12 Q. Well, do you recall that 13 Doctor Shulman had made recommendations 14 concerning the Fluoxetine clinical trials that 15 were adverse to a continuation of the Fluoxetine 16 clinical trials? 17 MR. MYERS: I object to the form. 18 Tell him if you know the answer. 19 A. I don't believe he ever made 20 such recommendations to me. 21 Q. That is that Doctor Shulman 22 made those recommendations to you. 23 A. That's correct. 24 Q. Who was everybody -- who were Page 271 1 you reporting to at that time, '78 and '79, in 2 connection with your work on Fluoxetine? 3 A. I don't understand what you 4 mean. Are you asking -- 5 Q. Who would have been making a 6 final decision on whether or not the clinical 7 trials would continue? 8 A. Okay. That decision would 9 have been made by a reviewing group made up of 10 top administrators in the research division and 11 it was called different things at different 12 times. So, I don't remember whether it was 13 called Research Project Committee in that year, 14 but it may have been. 15 Q. Well, who was Doctor Herr? 16 A. Would you spell that? 17 Q. H-E-R-R. 18 A. Doctor Herr was president of 19 Lilly Research Laboratories. 20 Q. Would he have been involved in 21 '78 or '79 in connection with continuing or 22 discontinuing the Fluoxetine project? 23 A. If he was president of Lilly 24 Research Laboratories during that year, he Page 272 1 certainly would have been. I don't remember the 2 year he became president of Lilly Research 3 Laboratories. 4 Q. How about Doctor Bennett? 5 A. Doctor Ivan Bennett? 6 Q. Yes. 7 A. Doctor Bennett probably was 8 not on the project team at that time. 9 Q. But would he have been -- what 10 was Doctor Bennett's position at that time? 11 A. I could not remember Doctor 12 Bennett's position that year. I can tell you 13 that Doctor Bennett was in the medical division, 14 had a fairly long career at Lilly and did a 15 variety of things during that career, but I could 16 not tell you what he was doing specifically in 17 1979. 18 Q. Was he at one time approving 19 expenditures for the Fluoxetine project? 20 A. I feel sure he wouldn't have 21 been during the time that Doctor Shulman was 22 here, he might have been at an earlier time. 23 Q. Doctor, do you recall going to 24 someone within the Lilly hierarchy in '78 or '79 Page 273 1 and complaining that -- or voicing your opinion 2 that the Fluoxetine project should not be 3 discontinued and that it should be continued for 4 a period of time? 5 A. I don't remember ever 6 discussing the issue of discontinuing. I do 7 remember discussing the issue of moving at a 8 faster pace. 9 Q. In what connection? 10 A. In connection with the 11 development of Fluoxetine. 12 Q. What pace were you trying to 13 move -- what pace were you at and what pace were 14 you trying to get to? 15 A. I was anxious that the 16 clinical trials be conducted more expeditiously. 17 Q. Why were you anxious to get 18 the clinical trials conducted more expeditiously, 19 Doctor Fuller? 20 A. Because we needed to find out 21 if the drug was effective in the treatment of 22 depression. 23 Q. Why was there a rush to do 24 that? Page 274 1 MR. MYERS: I object to the form. He 2 didn't say that there was a rush, you 3 mischaracterized what he said. 4 A. As I explained, that was the 5 mission of the project team to ensure that all 6 the studies were done that were necessary to 7 establish whether the compound was effective in 8 the treatment of depression. So, I was anxious 9 that we conduct our mission. 10 Q. Well, you said that you were 11 not happy about the pace at which the trials were 12 ongoing, is that right? 13 A. I don't remember that I 14 referred to my own happiness. 15 Q. Or you were concerned. Doctor 16 Fuller, I'm just trying to get through this, 17 okay, and I'm not going to hold you to a 18 particular phrase, all right, except in the 19 scientific area, like in terms like transporter 20 and receptors, I'm going to defer to you in 21 connection with scientific matters. But I don't 22 want to quibble with you about terms like happy 23 or things of that nature, I just want to get a 24 sense of what was going on in connection with the Page 275 1 development of this drug, all right? 2 MR. MYERS: What is the question? 3 Q. My question is, what were you 4 unhappy or dissatisfied or somewhat anxious about 5 the pace at which the clinical trials were 6 proceeding in connection with use of Fluoxetine 7 as an antidepressant in 1978 or '79? 8 A. The job of the project team 9 was to coordinate the studies that would tell us 10 if the compound was an effective and safe 11 antidepressant drug, and as chairman of the 12 project team, I wanted us to do our job. 13 Q. Was there a necessity that 14 that job be done quickly? 15 A. The whole point of doing that 16 job is to do it in a timely fashion. 17 Q. What was the reason for a 18 particular deadline at any particular time in 19 connection with the clinical trials or the 20 research concerning this drug? 21 MR. MYERS: I object to the form, he 22 didn't say there was a deadline. 23 A. I'm not aware of any such 24 deadlines. Page 276 1 Q. Well, you had expressed that 2 earlier, I believe, some dissatisfaction with 3 respect to the pace at which the trials were 4 proceeding, correct? 5 A. That's correct. 6 Q. And why were you dissatisfied 7 with the pace or why were you concerned about the 8 pace at which the trials were proceeding? 9 A. Because I wanted them to 10 proceed more rapidly. 11 Q. Why did you want them to 12 proceed more rapidly? 13 A. So that we would know the 14 answer as to whether the compound was an 15 effective antidepressant drug? 16 Q. Why did you want to know that 17 answer more rapidly? 18 A. That was the job of the 19 project team, to determine that answer. 20 Q. Was part of the job to 21 determine that answer quickly? 22 A. The job was to determine the 23 answer. 24 Q. Well, but you were concerned Page 277 1 in '78 or '79 about the pace at which that answer -- 2 that question was going to be answered. My 3 question is, what was the reason for having a 4 concern about the pace? 5 A. Because we needed to find out 6 if the compound was a safe and effective 7 antidepressant drug. 8 Q. Why did you need to determine 9 that at any particular time or on any particular 10 schedule or at any particular pace? 11 A. We simply needed to determine 12 that, and my job as chairman of the project team 13 was to try to ensure that everything was done 14 that needed to be done in order to find out the 15 answer to the question of whether Fluoxetine was 16 effective in treating depression. 17 Q. I understand that, Doctor 18 Fuller, but why was there a necessity to 19 determine that, the answer to that question at 20 any particular pace or speed? 21 A. I didn't say there was a 22 necessity to do that. 23 Q. You said you were concerned 24 about the pace at which the clinical trials were Page 278 1 proceeding in '78 or '79. 2 A. Yes. I was anxious to see 3 that the studies were done as soon and as well as 4 they could be. 5 Q. My question was simply why 6 were you anxious to see that the studies were 7 done as soon and as well as they could be? 8 MR. MYERS: That question has been 9 asked and answered about four times and I object 10 to form. 11 A. Whenever I have a 12 responsibility to do a job, I try to carry that 13 out as well and as quickly as possible. 14 Q. Was anybody putting pressure 15 on you, Doctor Fuller, to get this job done 16 quickly? 17 A. No. 18 Q. Was there any particular 19 reason to get this job done quickly? 20 A. In all of my research, I tried 21 to do it as effectively and as efficiently and as 22 quickly as possible, I don't like to waste time. 23 Q. I'm not talking about a 24 wasting of time, I'm talking about what is the Page 279 1 reason to do something quickly or, not anything, 2 what was the reason that you were concerned about 3 getting the Fluoxetine trials done quickly in 4 1978 or '79? 5 A. As with other work that I was 6 doing at that time -- 7 Q. I'm just concerned about the 8 Fluoxetine work, Doctor Fuller, and the 9 Fluoxetine clinical trials. In fact, the court 10 has asked us not to inquire about your other 11 work. 12 A. The job that I had as chairman 13 of the project team was to ensure that all of the 14 studies which are necessary to conduct clinical 15 investigations and determine if the drug is 16 effective in the therapeutic uses for which it is 17 intended. That was our responsibility as the 18 project team and my responsibility as the 19 chairman, to see that this work got done and 20 that's what I was trying to do. 21 Q. And in '78 and '79 you were 22 concerned about the pace at which this job was -- 23 this work was being done, is that correct? 24 A. From the beginning of the time Page 280 1 I was chairman of the project team to the end of 2 that time, I tried to see that everything got 3 done in as efficiently a way as possible, 4 including the clinical trials. 5 Q. Were you trying to get the job 6 done as quickly as possible? 7 MR. MYERS: I object to the form, he's 8 answered that two or three times. Answer it one 9 more time, Doctor Fuller. 10 A. I was concerned with seeing 11 that everything got done as well and as quickly 12 as possible. 13 Q. My question now is, the 14 reasons for your concern that the job be done as 15 quickly as possible. 16 A. I have the concern with 17 anything I'm asked to do that it be done as well 18 and as quickly as possible. 19 Q. So there wasn't any outside 20 pressure being brought to bear on you? 21 A. That is correct. 22 Q. To increase the pace of the 23 Fluoxetine clinical trials then? 24 A. That is correct. Page 281 1 Q. That's just part of your 2 nature to get things done as quickly and well as 3 possible? 4 A. That is correct. 5 Q. That's something that you were 6 generating within yourself? 7 A. That is correct. 8 Q. Had you complained to Doctor 9 Shulman about the pace at which the clinical 10 trial work was being done in 1978 and '79? 11 A. I don't remember that I did. 12 Q. Did you have any other 13 concerns in connection with the quality of Doctor 14 Shulman's work in the clinical trials? 15 MR. MYERS: I object to the form. 16 Concerns about quality, other than what? 17 MR. SMITH: Than pace. 18 MR. MYERS: Of the clinical trials? 19 MR. SMITH: Yes. 20 A. I'm sorry, could you restate 21 the question then? 22 Q. Did you have any other current 23 concerns about Doctor Shulman's work on the 24 clinical trials, other than the speed or the pace Page 282 1 that the trials were being conducted? 2 A. None that I remember. 3 Q. The reason I ask that, Doctor 4 Fuller, is we took Doctor Slater's deposition and 5 on page sixty-seven of that deposition, I asked 6 Doctor Slater, well, as I understand it from what 7 you said, Doctor Shulman's work, in the opinions 8 of you who were involved in the preclinical 9 studies, was not adequate, it had demonstrated 10 that Fluoxetine hydrochloride was not efficacious 11 in treating individuals who were depressed, is 12 that right. He said -- his answer was yes. 13 Question, and you and others in your group 14 believe that his work was either erroneous or had 15 not been done with enough insight or vigor to 16 demonstrate the efficacy of this product as an 17 antidepressant, his answer was yes. I then asked 18 him, who was joining you at this time in raising 19 these concerns with respect to the early Phase 2 20 clinical trials done by Doctor Shulman. His 21 answer was Doctor Fuller, Doctor Wong, Doctor 22 Molloy and so on, the people who had worked so 23 hard in the preclinical phase. Then I asked, how 24 did you and Fuller, Wong and Molloy voice your Page 283 1 concern in this connection, did you write memos, 2 did you write rebuttals to the clinical trials 3 that were done under Doctor Shulman, how did you 4 make this known. He said, I wouldn't swear to 5 the thing, but I think we did a great deal of 6 bitching around the company. My response was I 7 was trying to avoid saying that, even though 8 that's what I was hinting at. Then on page 9 seventy-six I asked, but there was some, I guess 10 I'm having trouble, how did Doctor Shedden come 11 up to review that decision, was there such an 12 uproar about the decision to kill the clinical 13 trials, that he had re-evaluated Doctor Shulman's 14 decision. His answer was, I really don't know. 15 I asked him, you just don't know that, answer, 16 that's his mind not mine. My question then was, 17 I thought there might have been a series of memos 18 or a series of discussions between maybe you and 19 Doctor Fuller, Wong and Molloy, in connection 20 with this. His answer was, we discussed it among 21 ourselves, but I don't know how word got around. 22 Now, with that as a source to 23 refresh your recollection, do you have now any 24 further remembrances concerning this problem with Page 284 1 Doctor Shedden, the problem with the clinical 2 trials and the problem of Doctor Shedden's 3 recommendation that the trials -- Shulman's 4 recommendations that the trials be discontinued 5 by virtue of the fact that the trials to that 6 point had proven that Fluoxetine was not 7 efficacious? 8 A. There were several things you 9 said in there which I think are untrue or 10 inaccurate. Could I have them read back so that 11 I can respond to them individually? 12 Q. Certainly. 13 MR. MYERS: Do you want the question 14 or the -- what he read from that transcript? 15 A. The question would be 16 sufficient. 17 (THE COURT REPORTER READ BACK THE 18 REQUESTED TESTIMONY.) 19 A. Okay, so your question about a 20 problem with Doctor Shedden was intended to be a 21 problem with Doctor Shulman? 22 Q. Yes. 23 A. I don't think I referred to 24 any problem with Doctor Shulman and I don't know Page 285 1 what you mean by that. 2 Q. Well, the problem that Doctor 3 Shulman -- right? 4 MS. ZETTLER: Yes. 5 Q. Was recommending discontinuing 6 the clinical trials on Fluoxetine because the 7 clinical trials up to that point had shown that 8 Fluoxetine was not efficacious as an 9 antidepressant? 10 MR. MYERS: Let me object to the form. 11 Are you asking him whether he recalls it the way 12 that Doctor Slater described it in his testimony, 13 is that what you want to know? Because you have 14 given him Slater's account. 15 MR. SMITH: I understand. 16 MR. MYERS: So is that the question, 17 does he recall it that way? 18 MR. SMITH: Yes. 19 A. Would you be satisfied if I 20 explained in my own words the situation that 21 existed at that time, in my mind, as I saw it? 22 Q. All right. 23 A. The way one finds out if a 24 drug is effective in depression or other Page 286 1 illnesses, is to have results of double-blind 2 controlled studies to determine if the compound 3 differs from a placebo group in the treatment of 4 that disease. Such studies had not been done, at 5 that point, so there was no proof or evidence 6 that the drug was effective or not effective. 7 That's what we needed to have were data of that 8 sort. The problem -- there was no problem with 9 Doctor Shulman in my mind. The problem, if there 10 was one, is that we didn't yet have definitive 11 data which would tell us whether the compound was 12 effective or not. The recommendation that you 13 allege Doctor Shulman to have made for 14 discontinuing the compound, is not something I 15 recall. It is possible that Doctor Shulman 16 expressed that opinion to someone or another, I 17 don't believe he expressed that opinion to me. 18 So far as I remember, there was not, at that 19 point, any serious discussion about discontinuing 20 the clinical trials, because I believe everybody 21 involved understood and recognized that we did 22 not yet have definitive data that would tell us 23 if the compound was effective or not and 24 therefore we needed to proceed toward getting Page 287 1 those data. 2 Q. Do you remember receiving 3 preliminary data that was inconclusive at least 4 concerning whether or not Fluoxetine would be 5 efficacious for treatment of depression? 6 A. Yes. 7 MR. MYERS: Your question is that same 8 time period '78-79? 9 MR. SMITH: Yes. 10 A. All of the data prior to the 11 double blind clinical trials were by their nature 12 inconclusive. 13 Q. Your work was inconclusive 14 then, up to that point? 15 A. I did not do any work related 16 to the clinical efficacy of Fluoxetine in 17 depression. The work we were discussing here is 18 clinical studies that were done to ascertain 19 whether Fluoxetine was effective in the treatment 20 of depression in humans. 21 Q. Do you believe that the work 22 you did, the experiments you did, were in any way 23 relevant to whether or not Fluoxetine would be 24 efficacious as an antidepressant in humans? Page 288 1 A. The work that I did in animals 2 was certainly relevant, in my opinion, to the 3 potential usefulness of Fluoxetine in the 4 treatment of depression. In order to find out if 5 Fluoxetine or any other drug is effective in 6 human beings who are afflicted with depression, 7 studies have to be done in human beings who are 8 afflicted with depression to find out if the drug 9 alleviates their symptoms. I did not do any such 10 research personally. 11 Q. What do you feel was the 12 contents of your studies that were relevant to 13 the issue of whether or not Fluoxetine would be 14 efficacious as an antidepressant in humans? 15 A. You're referring to studies 16 that I did as an individual? 17 Q. Yes. 18 A. Not studies that Lilly did, is 19 that correct? 20 Q. Yes. 21 A. The studies that I did were 22 concerned with showing that Fluoxetine was 23 effective in blocking the neuronal uptake of 24 serotonin and that it was selective in that Page 289 1 regard and that it was orally effective and had 2 an adequate duration of action. And that as a 3 consequence of that block of serotonin uptake, 4 that serotonergic function was increased. And 5 that work, when viewed in the context of the 6 understanding at that time of the role of 7 serotonin in depression and in the action of 8 antidepressant drugs led to the prediction that 9 Fluoxetine would be effective in the treatment of 10 mental depression in humans. 11 Q. But, the determination 12 concerning whether or not it would be efficacious 13 in treatment in humans was left up to the 14 clinical trials in humans? 15 A. That is the way to determine 16 if a compound is effective in treating mental 17 depression in humans. 18 Q. Did you draw a conclusion with 19 respect to whether or not Fluoxetine would be 20 efficacious in treatment of humans for depression 21 prior to the conclusion of the clinical trials? 22 MR. MYERS: Let me object to the form. 23 When you say the clinical trials, there have been 24 many and are many. At what point in time? Page 290 1 MR. SMITH: Up until 1985, when the 2 approvable letter was granted. 3 MR. MYERS: I object to the form, only 4 because I think you have your dates mixed up. 5 A. My conclusions about the 6 effect, any effect of Fluoxetine, are based upon 7 data and the conclusions about is the compound 8 effective in the treatment of mental depression 9 in humans, was made based upon data available 10 from studies of the effect of Fluoxetine on 11 mental depression in humans. 12 Q. When did you, in your opinion, 13 receive sufficient data to make that conclusion? 14 A. It was when the results became 15 available from the double-blind controlled 16 studies comparing Fluoxetine to placebo in human 17 subjects who were depressed. 18 Q. Do you recall when that was, 19 Doctor Fuller? 20 A. I don't recall the date of 21 that. 22 Q. Do you recall which particular 23 protocol it was that examined that issue in a 24 double-blind placebo study in humans? Page 291 1 A. If you're asking do I recall 2 the protocol number or that -- 3 Q. The particular protocol at all 4 in any way. 5 A. The general nature of the 6 protocol was what I just described. These were 7 double-blinded studies comparing Fluoxetine to 8 placebo after treatment for a period of some 9 weeks in patients who were depressed having 10 certain characteristics that were defined on the 11 basis of Hamilton rating scales and other scales 12 for measuring the severity of depressive 13 symptoms. 14 Q. Do you have a recollection of 15 seeing a specific piece of data and saying, okay, 16 we got our proof now, this is what we've been 17 looking for, now I am certain or reasonably 18 certain, from a scientific standpoint, that this 19 data supports my belief up to that point that 20 this would be an efficacious treatment of 21 depressed individuals? 22 A. Yes. When the results of that 23 multi-center double-blind study comparing 24 Fluoxetine to placebo in depressed patients Page 292 1 became available, when those results were 2 tabulated and analyzed statistically, then it was 3 clear that the compound seemed to be effective as 4 an antidepressant drug. 5 Q. All right. 6 MR. MYERS: Can we take a break? 7 MR. SMITH: Yes. 8 (A SHORT RECESS WAS TAKEN.) 9 Q. Do you disagree with the 10 statements made by Doctor Slater in connection 11 with the problems with Doctor Shulman? 12 A. What statement do you have in 13 mind? 14 Q. Well, on page 67 of his 15 deposition, I asked him, well, as I understand 16 it, from what you said, Doctor Shulman's work in 17 the opinions of you who were involved in the 18 preclinical studies was not adequate, it had 19 demonstrated that Fluoxetine Hydrochloride was 20 not efficacious in treating individuals who were 21 depressed, is that right. His answer was, yes. 22 Do you disagree with Doctor 23 Slater's statement there? 24 A. I disagree with your Page 293 1 statement, I wouldn't have responded with a yes 2 as Doctor Slater did. 3 Q. So, Doctor Slater is -- was 4 incorrect when he responded to my statement with 5 a yes, in your opinion? 6 A. No, I wouldn't say that. I 7 simply said that isn't the way I would have 8 answered it. 9 Q. Do you disagree that Doctor 10 Shulman's work in the preclinical studies was not 11 adequate? 12 MR. MYERS: Hold on, let me object to 13 the form, because I don't -- I'm going to object 14 to the form, Paul, because what you're reading 15 him doesn't say that Doctor Shulman did any 16 preclinical studies. What it says is something 17 about those of you who were involved in the 18 preclinical studies, so I don't know if you made 19 that connection or not. 20 MR. SMITH: You got your objection. 21 A. What was not adequate were the 22 amount of data available at the time to make a 23 decision, it had not been demonstrated that 24 Fluoxetine was not efficacious in treating Page 294 1 individuals who were depressed. That simply -- 2 there simply were no data that were adequate to 3 make a judgment as to whether Fluoxetine was 4 efficacious or not. That is -- that I would not 5 describe as Doctor Shulman's work not being 6 adequate, but rather that the amount of data that 7 were available at that time were not adequate to 8 make a decision about the efficacy of Fluoxetine 9 in treating depression. 10 Q. So, you wouldn't agree with 11 Doctor Slater's affirmative answer to that 12 statement? 13 A. I would not have made an 14 affirmative answer to that statement myself. 15 Q. On page -- on line 10 of page 16 67, I asked, and you and others in your group 17 believe that his work was either erroneous or it 18 had not been done with enough insight or vigor to 19 demonstrate the efficacy of this product as an 20 antidepressant, and he answered yes. Correct -- 21 correct that he answered yes? 22 MR. MYERS: He wants to know if he 23 read it correctly. 24 A. You read it correctly from the Page 295 1 transcript. 2 Q. Now obviously that was Doctor 3 Slater expressing his opinion in connection with 4 the work of Doctor Shulman being erroneous or not 5 being done with enough insight or vigor, correct? 6 A. I'm willing to believe that 7 you are reading from a transcript of Doctor 8 Shulman's deposition, yes. 9 Q. All right. Now I'm going to 10 ask you, do you believe that Doctor Shulman's 11 work was erroneous? 12 A. As I have explained, I believe 13 that the amount of data that were available at 14 that time were insufficient to make a decision 15 about the efficacy of Fluoxetine. That is not 16 suggesting that anyone's work is erroneous. So 17 that statement that you made is not a statement 18 that I would have agreed with. 19 Q. So, you would not agree that 20 Doctor Shulman's work was erroneous? 21 A. Doctor Shulman, of course, 22 didn't do clinical studies on his own. What 23 Doctor Shulman did was engage competent qualified 24 investigators at various medical centers around Page 296 1 the country to actually do the clinical studies 2 on Fluoxetine. So, I simply don't know what 3 particular part of Doctor Shulman's work you 4 would be referring to in describing it as 5 erroneous, I would have to understand that better 6 before I could make a judgment as to whether it 7 could be a correct statement or not. 8 Q. So, you're just not going to 9 to answer that question -- 10 MR. MYERS: I object to the form. 11 Q. -- with a yes or no answer. 12 MR. MYERS: He's answered it as best 13 as he can with you taking excerpts from a 14 deposition. He's answered that. 15 MR. SMITH: Is that an objection? 16 MR. MYERS: That is an objection, yes, 17 that he's answered it. 18 Q. Go ahead and give me your 19 answer to my question, Doctor Fuller. 20 A. I tried to answer your 21 question in the most informative and helpful way 22 that I can. 23 Q. You don't believe that Doctor 24 Shulman's work was erroneous? Page 297 1 MR. MYERS: I object to the form, 2 asked and answered. 3 A. What work are you referring 4 to? 5 Q. The work that Doctor Shulman 6 did in connection with research and clinical 7 studies, in connection with the efficacy of 8 Fluoxetine as an antidepressant, Doctor Fuller. 9 A. The work that I know of that 10 Doctor Shulman did consisted of arranging for 11 clinical trials to be done at various medical 12 centers. 13 Q. Do you know whether he did any 14 erroneous work in that respect? 15 A. I frankly don't understand 16 what you mean by erroneous in the context of that 17 sort of work. 18 Q. Do you know of any errors he 19 made in that respect? 20 A. You mean misspelling of 21 clinical investigators' names or do you mean 22 things of that nature or -- 23 Q. Any errors, whether it be 24 misspelling or coming to wrong conclusions, do Page 298 1 you know of any errors Doctor Shulman did? 2 A. So far as I know, Doctor 3 Shulman didn't come to any conclusions because 4 the data were not adequate to permit that. 5 Q. Do you know of any errors he 6 made, Doctor Fuller? 7 A. I am not aware of errors that 8 Doctor Shulman made. 9 Q. Okay. Do you have an opinion 10 whether or not Doctor Shulman was doing his work 11 with enough insight? 12 A. Doctor Shulman enlisted the 13 help of very prominent and qualified clinical 14 investigators in the design of the clinical 15 studies that were done. 16 Q. I'm not talking about work 17 that somebody else would have done, Doctor 18 Fuller, I'm talking about Doctor Shulman and his 19 work himself. Do you know of any work that he 20 did that was not done with enough insight, that 21 Doctor Shulman did that did not have enough 22 insight? 23 A. The work -- it was work that 24 Doctor Shulman did to enlist those investigators. Page 299 1 He showed insight in choosing the investigators 2 to participate in the design of the clinical 3 study and they provided insight from their 4 clinical experience in the design of those 5 studies. So -- 6 Q. Do you have any complaints 7 with that? 8 MR. MYERS: Wait a minute, let him 9 finish. If you weren't finished, Doctor Fuller, 10 finish. 11 A. So, there was insight to the 12 project that was supplied by all of those people. 13 Again, the work that you are referring to that 14 Doctor Shulman did, I think was in the selection 15 of those investigators and so far as I know, he 16 used insight in choosing those investigators. 17 Q. Okay. So, you don't have any 18 problems with the insight he exercised in 19 choosing those investigators? 20 A. No, I don't. 21 Q. Do you have any problem or 22 quarrel with the conclusions that any of the 23 investigators that he selected rendered? 24 A. I don't know what conclusions Page 300 1 they rendered. 2 Q. You don't? 3 A. No. 4 Q. Do you know what data they 5 assimilated? 6 A. I know that they assimilated 7 some data from open label preliminary exploratory 8 studies with Fluoxetine, yes. 9 Q. Do you have any problem with 10 any of the data that they generated? 11 A. No. So far as I know, they 12 are typical exploratory preliminary data. 13 Q. And you wouldn't disagree with 14 anything that any of those clinical investigators 15 did, or you don't have any recollection of 16 anything that you disagreed with in connection 17 with what they did? 18 A. I don't remember anything that 19 they did which I disagreed with. 20 Q. All right. Did you share 21 Doctor Slater's opinion that Doctor Shulman's 22 work was not being done with enough vigor to 23 demonstrate the efficacy of the product as an 24 antidepressant? Page 301 1 A. As I explained earlier, there -- 2 it was my concern that the adequate data be 3 obtained as soon as possible, to determine if the 4 compound was effective. And that meant that 5 double-blind studies needed to be instituted as 6 soon as possible, and I thought that that should 7 be moving as rapidly as possible. I have no 8 reason to doubt that Doctor Shulman was doing his 9 best in getting those studies done, but they 10 hadn't been done yet at that time. 11 Q. Do you believe he was moving 12 with the proper vigor in getting this done? 13 MR. MYERS: When you say getting this 14 done, you mean the double-blind studies? 15 Q. Getting what he was supposed 16 to be doing done. 17 MR. MYERS: Well, that's a different 18 question. 19 A. I don't know that that is a 20 judgment that I could make, to be honest. 21 Q. Okay. All right, so, when 22 Doctor Slater says, when I asked him, who was 23 joining you at this time in raising these 24 concerns with respect to the early Phase 2 Page 302 1 clinical trials done by Doctor Shulman, and he 2 says Doctor Fuller, Doctor Wong, Doctor Molloy 3 and so on, the people who had worked so hard in 4 the preclinical phases, is he incorrect when he 5 said that you were joining him in raising your 6 concerns concerning these matters? 7 A. I think he is correct in 8 saying that we were all concerned that 9 double-blind clinical data needed to be obtained 10 as soon as possible to determine whether 11 Fluoxetine was safe and effective. 12 MR. MYERS: Let him finish, Paul. If 13 you're not finished, Doctor Fuller, finish your 14 answer and then ask him another question. 15 A. What I was saying was, that I 16 think we were all concerned that we needed to 17 have double-blind clinical data more rapidly than 18 we were getting them and that what -- where I 19 would disagree with Doctor Slater is in agreeing 20 with the terminology that you used which focused 21 I think erroneously on problems with Doctor 22 Shulman. The problems were with the 23 unavailability of definitive data. 24 Q. He doesn't say anything at all Page 303 1 in that area, does he, about the unavailability 2 of definitive data, does he? 3 MR. MYERS: Let me object to the form. 4 Is the question -- is there a statement to that 5 effect on the page you read from? 6 MR. SMITH: Yes. 7 A. Doctor Slater's two words here 8 are yes and yes. 9 Q. Well, I don't say anything in 10 my questions to him to which he replied yes and 11 yes about availability or unavailability of 12 doubled-blind data, do I? 13 A. That's correct, you don't. 14 MR. MYERS: Paul, we can all hear you, 15 so don't raise your voice with the witness, we 16 can hear you. 17 Q. As the chairman of the project -- 18 as the chairman of the Fluoxetine project team, 19 did you ever express any criticism of any nature 20 to Doctor Shulman? 21 A. I simply don't remember 22 fifteen years ago whether I said anything to 23 Doctor Shulman or not that was critical in 24 nature. It's certainly possible that I did and Page 304 1 it's possible that I didn't. 2 Q. As we sit here today, do you 3 have any recollection of any criticism of Doctor 4 Shulman's work as the medical monitor on this 5 project? 6 A. You are now asking me a 7 different question, is that correct that -- I 8 think the pace at which Doctor Shulman was able 9 to organize clinical studies was slower than it 10 might have been and that we might have been able 11 to obtain double-blind controlled data more 12 rapidly had he been an investigator who had prior 13 experience in organizing studies like that. 14 Q. Did you express that to him? 15 A. I don't believe I did. I 16 think he -- I think I understood that he was 17 aware of his lack of experience in having done 18 that before and I probably judged that such a 19 statement would not be helpful. 20 Q. Did you express it to anybody 21 else? 22 A. It's quite possible that I 23 did, I don't remember specifically that I did. 24 Q. Do you think it's quite Page 305 1 possible that you expressed that to Doctor 2 Slater? 3 A. It's certainly possible. 4 Q. Do you recall, Doctor Fuller, 5 doing any bitching, as Doctor Slater expressed, 6 concerning concerns at the time with the work of 7 Doctor Shulman? 8 A. No, I don't remember doing 9 that. 10 Q. I would like to go over some 11 more of Doctor Slater's testimony with you, 12 Doctor Fuller, and I have the complete copy of 13 the transcript that was done on January 28th, 14 1994. This is a -- 15 A. May I point out an error? 16 Q. Feel free. 17 A. That is the wrong degree for 18 Doctor Slater. 19 Q. He is an M.D.? 20 A. Yes. 21 Q. Yes. We will have to talk to 22 the court reporter that did that, probably we'll 23 have to discipline the court reporter in some 24 manner. Page 306 1 On page 78 of Doctor Slater's 2 deposition, I asked him on line 8, question, so 3 was there the thought of discontinuing clinical 4 trials on the Fluoxetine Hydrochloride completely 5 at this time. His answer was, they had been 6 completely discontinued. I then asked him, when 7 was that that they completely discontinued the 8 early Phase 2 clinical trials. His answer was 9 1977. My question then was, who would have been 10 responsibility for making that decision. His 11 answer was Doctor Shulman. 12 My question to you, Doctor 13 Fuller, is, were the clinical trials on 14 Fluoxetine Hydrochloride completely discontinued? 15 MR. MYERS: At the -- at the point in 16 time referenced there or some other time? 17 Q. Of any time, prior to there 18 being -- at any time. 19 A. Based on what you've just 20 shown me, I think Doctor Slater probably 21 understood something different by completely 22 discontinued than what I would interpret that you 23 mean. If you mean was there a decision not to do 24 any further clinical studies, that decision had Page 307 1 not been made. If you mean were there actually 2 any clinical studies going on on a particular day 3 or week at this time, it's quite possible that 4 there were not, but that isn't to say that the 5 intent was not to institute others. Do you 6 understand my point? 7 Q. Yes, I understand your point 8 exactly. You're saying, are you not -- or are 9 you saying that Doctor Slater is wrong when he 10 says the decision had been made in 1977 to 11 completely discontinue the Phase 2 clinical 12 trials? 13 A. What I'm saying is that Doctor 14 Slater made no such statement, according to this 15 transcript. 16 Q. He did in his deposition. 17 A. May I read it? 18 Q. Sure. 19 A. What Doctor Slater said 20 according to this is that they had been 21 completely discontinued. He did not say that 22 there had been a decision made to not do any 23 further clinical studies. I imagine what he 24 meant was that there were not any studies going Page 308 1 on at that particular time. 2 MR. SMITH: Let me object to that 3 answer as being nonresponsive and it would be 4 drawing -- would be speculative on this witness's 5 part concerning what Doctor Slater meant. 6 MS. ZETTLER: Mischaracterizes the 7 testimony of Doctor Slater also. 8 MR. MYERS: You just don't like the 9 answer as responsive. 10 MR. SMITH: I don't like your side bar 11 remarks, either. 12 MR. MYERS: You just don't like the 13 answer. If you're going to ask him about the 14 transcript, Mister Smith, that's fine, if you're 15 going to ask him if he recalls that that was the 16 way things were at that time, that's fine. 17 Q. The transcript does say, does 18 it not, Doctor Fuller, question, so was there the 19 thought of discontinuing clinical trials on 20 Fluoxetine Hydrochloride completely at that time, 21 the answer there says they had been completely 22 discontinued. The next question is, when was 23 that they completely discontinued the early Phase 24 2 clinical trials, the answer is 1977. The next Page 309 1 question was, who would have been responsible for 2 making that decision, and his answer is Doctor 3 Shulman. Is that what the transcript says? 4 A. Yes, it is. 5 Q. Is Doctor Slater incorrect 6 when he says that they completely discontinued 7 the early Phase 2 clinical trials in 1977? 8 A. That isn't what the transcript 9 shows Doctor Slater said. 10 Q. Well, it's the question and 11 answer, isn't it? 12 A. The transcript shows that 13 Doctor Slater said they had been completely 14 discontinued. 15 Q. In 1977. 16 A. No, I'm sorry, that isn't what 17 the transcript states. The transcript states 18 that Doctor Slater responded to your question 19 which was, so was there thought of discontinuing 20 clinical trials on Fluoxetine Hydrochloride 21 completely at this time, Doctor Slater's answer 22 was they had been completely discontinued, and in 23 response to your question when was that that they 24 completely discontinued the early Phase 2 Page 310 1 clinical trials, Doctor Slater's answer was 1977. 2 Q. Then I went ahead and asked 3 him, who would have been responsible for making 4 that decision and his answer is Doctor Shulman, 5 isn't it? 6 A. That's correct. 7 Q. Is any part of that that's 8 incorrect? 9 MR. MYERS: You want to know if any of 10 the answers to those three questions are 11 erroneous, as far as Doctor Fuller knows? 12 MR. SMITH: Yes. 13 A. As I explained, the -- if, by 14 your question, you mean that clinical trials had 15 been discontinued with the thought of not doing 16 any further clinical trials, then I believe that 17 is not the correct response. If you meant 18 something else, perhaps Doctor Slater understood 19 it better than I do and perhaps his response was 20 correct. 21 Q. Do you recall Doctor Shedden 22 coming in and overriding Doctor Shulman's 23 decision to completely discontinue the clinical 24 trials? Page 311 1 MR. MYERS: Before he answers, let me 2 object to the form, only to the extent I don't 3 know that he's testified that Doctor Shulman 4 discontinued the trials. I don't know that he 5 said that or not. I know that's what that 6 transcript may say from Doctor Slater, but I 7 don't know that Doctor Fuller has testified to 8 that. 9 Q. Can you answer my question? 10 A. To the best of my 11 recollection, there was never any decision to 12 discontinue clinical trials in the sense of not 13 doing any further clinical trials. There were 14 individual decisions to discontinue individual 15 clinical trials as they were completed. Doctor 16 Shulman was not in a position to make any binding 17 decision about the doing or not doing of future 18 clinical trials. So, I don't know what you were 19 referring to in Doctor Shedden overriding Doctor 20 Shulman's decision. If there was a decision 21 about an individual clinical trial that Doctor 22 Shulman had made, I don't remember it. 23 Q. Well, maybe we can get at it 24 this way. Page 312 1 MR. MYERS: I doubt it, but let's try 2 it. 3 MR. SMITH: Check your side bar 4 remarks, Counsel. 5 MR. MYERS: Noted. 6 Q. On page 73 of Doctor Slater's 7 deposition, I asked him on line 2, question, why 8 did you become the medical monitor or clinical 9 trial administrator of Fluoxetine Hydrochloride 10 in 1978. His answer was, Doctor Shulman had done 11 very few studies and had determined that he was 12 unable to demonstrate any clinical efficacy, we, 13 in pharmacology and in the preclinical research 14 component, were very unhappy because we felt that 15 these studies had been inadequate and we made our 16 unhappiness known, when there was a 17 reorganization in which I was totally removed 18 from administrative responsibility, the director 19 of medical research indicated that since I was 20 going to retire in another year, would I be 21 willing, during the last year of my employment, 22 to make some attempt to determine whether the 23 company should or should not have further 24 interest in Fluoxetine, is that clear. My Page 313 1 question then was yes, in response to his 2 question. Then I asked him who was that 3 individual. His answer was the name is Doctor 4 Ian Shedden. I asked him then, what was Doctor 5 Shedden's title at the time. His answer was, he 6 was vice-president in charge of medical affairs, 7 this may not be accurately his title but defines 8 his responsibilities as I remember them. 9 Did I read that accurately, 10 Doctor Fuller? 11 A. I think you did. 12 Q. Do you agree or disagree with 13 Doctor Slater's statement that we in pharmacology 14 and in the preclinical research components were 15 very unhappy because we felt that these studies 16 had been inadequate and we made our unhappiness 17 known? 18 A. To the extent that I 19 understand his remark to mean we were unhappy 20 that there were no -- still not available any 21 double-blind clinical study data and, therefore, 22 it was not possible to make a decision as to 23 whether Fluoxetine was effective or not, at that 24 time, then I would certainly agree with that Page 314 1 statement. 2 Q. Do you recall that there was a 3 reorganization which Doctor Slater was totally 4 removed from administrative responsibilities? 5 A. Yes, I remember that. 6 Q. And that he accepted this 7 during his last year prior to retirement, to make 8 some attempt to determine whether the company 9 should or should not have further interest in 10 Fluoxetine? 11 A. With the stipulation that I 12 don't think I was aware that it was his last year 13 prior to retirement, that was a decision that he 14 made, but I am aware that he became clinical 15 monitor, yes. 16 Q. I understand that. And were 17 you aware that when he was clinical monitor that 18 the issue was whether or not there should be some 19 attempt -- he would be making some attempt to 20 determine whether or not the company should or 21 should not have further interest in Fluoxetine? 22 A. That is equivalent to saying, 23 should determine if it is effective in treating 24 mental depression. If it was effective, then Page 315 1 there would be further interest, and if it should 2 conclusively be shown not to be effective, then 3 there would not be further interest. 4 Q. By that, do you mean that had 5 the studies in that last year that Doctor Slater 6 worked for Eli Lilly and Company not indicated 7 efficacy in treatment of depression that 8 Fluoxetine would have been dropped at that point? 9 A. No. 10 Q. By Lilly? 11 A. That is not what I said. What 12 I said is that a decision would be made when 13 there were clinical data available to 14 conclusively demonstrate whether the compound was 15 or was not effective in the treatment of mental 16 depression. 17 Q. Do you know if that data 18 arrived before Doctor Slater left? 19 A. My recollection is that those 20 data were not available until after Doctor Slater 21 had left. 22 Q. How long were your rat 23 studies? 24 A. Which rat studies? Page 316 1 Q. What was the longest of any 2 rat studies you did in connection with 3 Fluoxetine? 4 A. I don't remember that for 5 sure. It would have been a matter of a few 6 weeks. 7 Q. Two weeks? 8 A. A few weeks. 9 Q. What do you mean by a few 10 weeks? 11 A. Somewhere between two and ten. 12 (PLAINTIFFS' EXHIBIT 7 WAS 13 MARKED FOR IDENTIFICATION AND 14 RECEIVED IN EVIDENCE.) 15 Q. Take a minute to review 16 Exhibit 7. I'm sorry, have you had an 17 opportunity to read Exhibit 7, Doctor Fuller? 18 A. Yes. 19 Q. This is a memo dated March 20 20th, 1987, it appears to me, is that correct? 21 A. That is the way it appears to 22 me. 23 Q. It looks like it's authored by 24 a J. L. Emmerson, does it not? Page 317 1 A. I think that being the name at 2 the bottom, it would be my interpretation. 3 Q. Do you know who J. L. Emmerson 4 is? 5 A. Yes, I do. 6 Q. Who is J. L. Emmerson? 7 A. He is in our Toxicology 8 Division? 9 Q. It looks like it potentially 10 is directed to Doctor R. H. Bishara, is that 11 correct? 12 A. That being the name at the 13 top? 14 Q. Yes. 15 A. That would be my 16 interpretation. 17 Q. Who is Doctor Bishara? 18 A. His name is Rafik Bishara, he 19 is a Ph.D scientist. I do not know for sure what 20 his position was in 1987. 21 Q. What is his position now? 22 A. I do not know that either. 23 Q. Do you know whether he still -- 24 was he an employee with Eli Lilly and Company in Page 318 1 1987? 2 A. Yes, he was and is an employee 3 with Eli Lilly and Company, but he is not someone 4 I know well. 5 Q. Do you know if Doctor Bishara 6 is in Indianapolis? 7 A. No, I don't know. 8 Q. Do you recall whether or not 9 Doctor Bishara was ever a resident in Japan? 10 A. No, I don't know. 11 Q. Do you know if Doctor Bishara 12 is of Japanese ancestry? 13 A. I'm reasonably certain he is 14 not. 15 Q. Is he Oriental? 16 A. I don't think so. 17 Q. It looks like this exhibit was 18 copied to Doctor M. E. Amundson, who is he? 19 A. He has retired from Lilly. He 20 was probably, at that time, in the Toxicology 21 Division as well. 22 Q. What was his title upon 23 retirement? 24 A. I do not remember. Page 319 1 Q. Was he a vice-president? 2 A. No, I don't believe so. 3 Q. Do you know, and I guess 4 you'll have to accept my representation, Doctor 5 Fuller, that this came from your file. Do you 6 know why this document would have been in your 7 file? Because the reason I asked that is because 8 you're not listed as one who was to receive a 9 carbon copy. 10 A. That is correct and therefore, 11 no, I don't know why it was in my file. 12 Q. Look with me at the next to 13 the last paragraph on page 1. It says a general 14 comment is in order. The list of studies shown 15 above is not necessarily complete. There is a 16 level of concern in Japan about drug induced 17 phospholipidosis that is not found in other parts 18 of the world. It is probable that additional 19 work would have been done to clarify this issue 20 for Japan. Correct? 21 A. No, not quite correct. The 22 word is phospholipidosis and the last sentence is 23 it is probable that additional work would have to 24 be done to clarify this issue for Japan. Page 320 1 Q. All right. Does this memo 2 appear to be talking about Japanese requirements 3 with respect to toxicology studies? 4 A. That would be my 5 interpretation. 6 Q. And filing a new drug 7 application with respect to Fluoxetine in Japan? 8 MR. MYERS: Or whatever they call it. 9 A. That would appear to be the 10 case. 11 Q. Well, it says NDA, I assume 12 that means new drug application, up in the first 13 paragraph. 14 A. I think in Japan it maybe 15 called something different, but I think that's 16 the idea. 17 Q. They refer to it as a NDA in 18 this memo, don't they, on the first paragraph? 19 A. Doctor Emmerson refers to it 20 as an NDA, yes. 21 Q. And the title of the memo is 22 Fluoxetine registration in Japan, is it not? 23 A. Yes, it is. 24 Q. The last paragraph of that Page 321 1 document says, we have also found that with other 2 compounds that the Japanese companies like to see 3 a 90-day subchronic rat study done precisely to 4 Japanese guidelines. Do you know if you in your 5 studies or anybody else at Eli Lilly and Company, 6 did a 90-day rat study? 7 MR. MYERS: Let me object to the form 8 of the question and maybe just ask, do you mean a 9 90-day rat study or a 90-day subchronic rat study 10 as it's described here? I don't know that 11 they're different, but they may be. 12 Q. Did you do any study involving 13 rats that encompassed a 90-day period of time? 14 A. Are you asking me did I do 15 such studies? 16 Q. We will start with that. 17 A. No. 18 Q. Do you know whether or not 19 anybody at Lilly did rat studies? 20 A. Yes, there were -- there was a 21 90-day subchronic rat toxicology study done 22 within the toxicology division? 23 Q. You are aware of that for 24 sure? Page 322 1 A. Yes, I am. 2 Q. Would that have been done 3 under your direction as Fluoxetine project 4 chairman -- team chairman? 5 A. No, my job as project team 6 chairman was not to direct such studies, my job 7 was simply to ensure that the responsible 8 division, namely the toxicology division, did 9 those studies. 10 Q. So you were responsible to see 11 that the proper division did the study. 12 A. Yes. 13 Q. The next sentence says, many 14 of the toxicology studies on Fluoxetine were 15 conducted in the early 1970's, the design of 16 these studies will not meet current Japanese 17 guidelines nor were these studies conducted under 18 the U.S. GLP regulations. Is that what it says? 19 A. That is what it says. 20 Q. Do you know what Doctor 21 Emmerson means by U.S. GLP regulations? 22 MR. MYERS: Before he answers, let me 23 object to the form as to what Doctor Emmerson 24 means by something, that would be speculation. Page 323 1 MR. SMITH: You're doing pretty good 2 in speculating what Doctor Slater meant and what 3 I meant in the deposition. 4 MR. MYERS: He was just trying to 5 answer your defective questions. 6 A. I think I know what he meant, 7 yes. 8 Q. All right, tell us. 9 A. I think he meant United States 10 for the U.S. and that he meant good laboratory 11 practices for the GLP. 12 Q. Were you aware that the 13 toxicology studies done on Fluoxetine in the 14 early '70's, did not meet U.S. good laboratory 15 practices regulations? 16 MR. MYERS: Let me object to the form 17 to the extent your question assumes that such a 18 regulation or regulations were in place at the 19 time and I don't know that there has been any 20 testimony one way or another. 21 A. I believe that the U.S. GLP 22 regulations came into effect later, so that so 23 far as I would believe, there were no studies 24 done in the early 1970's that would have been Page 324 1 done under U.S. GLP regulations in as much as 2 they didn't exist at the time. 3 Q. After the GLP regulations went 4 into effect, did you become conversant with what 5 those regulations required, Doctor Fuller? 6 A. Those regulations did not 7 apply to my research so I certainly was not 8 conversant with them. 9 Q. Then how do you know when they 10 came into effect and whether or not Lilly's 11 research in the early 1970's met those 12 guidelines? 13 A. That's why I said I believe 14 they were not. In fact, I do not recall the year 15 that the studies went into effect, but to the 16 best of my recollection, when they went into 17 effect all toxicology studies done at Lilly were 18 done under those regulations. 19 Q. Did Lilly have to change the 20 manner in which they were doing the toxicology 21 studies after the United States prescribed 22 regulations entitled U.S. good laboratory 23 practices? 24 A. I think fundamentally most of Page 325 1 the toxicology studies done at Lilly were done 2 under procedures that were at least as rigorous 3 as those spelled out in the GLP regulations, and 4 that fundamentally there were no changes in the 5 way those studies were conducted, but that there 6 probably were specific details which were 7 included in those regulations that may have been 8 different than in the studies done prior to the 9 establishment of those regulations. 10 Q. Do you disagree that many of 11 the toxicology studies on Fluoxetine that were 12 conducted in the early 1970's, did not meet U.S. 13 GLP regulations? 14 A. There are two statements here. 15 The first of them says that many of the 16 toxicology studies on Fluoxetine were conducted 17 in the early 1970's, and I believe that is true. 18 The statement about the design of these studies 19 was made by someone in the toxicology division 20 who knows far more about them than I would know. 21 Q. So you would have to defer to 22 him when he says the design of these studies will 23 not meet current Japanese regulations, nor were 24 these studies conducted under U.S. GLP Page 326 1 regulations? 2 A. I would certainly defer to 3 Doctor Emmerson. 4 Q. Are you aware of any efforts 5 made by the toxicology division to make changes 6 that would cause them to comply with U.S. GLP 7 regulations once those regulations went into 8 effect? 9 A. My knowledge would not be very 10 specific, but I believe that indeed the 11 toxicology division ensured that their studies 12 met all of the U.S. GLP regulations as soon as 13 they came into effect. 14 Q. But Doctor Emmerson is here 15 stating in this paper, this memo, that the early 16 1970 toxicology studies on Fluoxetine did not 17 meet U.S. GLP regulations, isn't he? 18 A. Yes, he is. 19 Q. Were you aware that in the 20 early '70's the studies that were being done in 21 the toxicology section at Eli Lilly and Company 22 did not fall under U.S. GLP regulations? 23 MR. MYERS: At what point? 24 MR. SMITH: In the early '70's, when Page 327 1 they were done. 2 A. As I explained to you earlier, 3 to the best of my recollection, the U.S. GLP 4 regulations didn't exist in the 1970's, so I'm 5 sure I wouldn't have thought about them. 6 Q. When did the U.S. GLP 7 regulations come into effect? 8 A. I do not know. I interpret 9 from this memo that it was sometime after that. 10 Q. Well, it says the design of 11 these studies will not meet current Japanese 12 guidelines, doesn't it? 13 A. That's exactly what it says. 14 Q. And then it says, nor were 15 these studies conducted under U.S. GLP 16 regulations. 17 A. We established that's what it 18 says. 19 Q. So, it's unclear whether or 20 not the U.S. GLP regulations were in place in the 21 early '70's -- 22 MR. MYERS: I object to the form. 23 Q. -- isn't it? 24 MR. MYERS: I object to the form, that Page 328 1 mischaracterizes his testimony. He testified to 2 something else. 3 A. This memo doesn't address the 4 question of when the U.S. GLP regulations came 5 into effect. 6 Q. What were the purposes of good 7 laboratory practices regulations when they came 8 into effect? 9 A. I had nothing to do with 10 writing those regulations or defining their 11 purposes. 12 Q. Were you aware of them, 13 whether you had anything to do with them or not, 14 were you aware of them? 15 A. I am, as I testified earlier, 16 generally aware of them, but I have very little 17 specific knowledge of them because they don't 18 apply to the kind of research that I do. 19 Q. Is it your testimony that it's 20 your understanding that U.S. good laboratory 21 practice regulations only apply to toxicology and 22 don't apply to animal research as you were doing 23 and as you do? 24 A. No, that is not my testimony. Page 329 1 Q. All right. What is your 2 testimony in that connection? 3 A. That good laboratory practice 4 regulations do not apply to the kind of basic 5 laboratory research that I'm involved in. 6 Q. Why? 7 A. I could not answer that, I do 8 not -- 9 Q. How do you know that these 10 practices do not apply? 11 MR. MYERS: Let him finish. Finish 12 your earlier answer before you answer the 13 question he just asked. 14 A. The U.S. GLP regulations were 15 established by the United States Government and I 16 do not know why they chose to apply them to some 17 areas. 18 Q. Well, how do you know that 19 they haven't applied them to your areas, Doctor 20 Fuller, don't you use laboratories? 21 A. Yes, I use laboratories. 22 Q. Then has somebody told you or 23 have you read the regulations, what leads you to 24 believe that the U.S. GLP regulations don't apply Page 330 1 to your type of research? 2 A. I've been told that and I 3 understand that from the fact that -- well, I've 4 been told that and I think I read that. 5 Q. Who told you that? 6 A. I don't remember. I think 7 it's fairly common knowledge. 8 Q. What about your work in the 9 laboratory exempts you or your type of work from 10 the GLP, United States GLP regulations? 11 MR. MYERS: Before he answers, let me 12 object to the form. What is or isn't included is 13 a matter of what's in the statute. The statute 14 says what it says, includes or excludes certain 15 things. If you have some independent 16 understanding, Doctor Fuller, tell Mister Smith. 17 A. I'm sorry, would you repeat 18 the question? 19 Q. Yes. Why is it -- what is it 20 about your work or what is it about the 21 regulations, that it excludes your work from the 22 GLP regulations and makes toxicology currently 23 subject to GLP regulations? 24 A. I think the gist of the matter Page 331 1 is that these regulations would apply to studies 2 that are conducted primarily to document the 3 safety of a compound and that is not the purpose 4 of my research. 5 Q. Okay. So, the toxicology 6 studies that were done by Lilly in the 1970's, 7 would not have met with the requirements of the 8 Good Laboratory Practices Act in connection with 9 safety or determining safety of the particular 10 study? 11 MR. MYERS: I object to the form, to 12 the extent your question assumes they did apply 13 to those studies. If you can answer the 14 question, Doctor, answer it. 15 A. From the Exhibit that you have 16 shown me, Number 7, it would appear that the GLP 17 regulations came into effect after the early 18 1970's, when the toxicology studies that are 19 referred to here on Fluoxetine were done and 20 certainly studies done before regulations came 21 into effect, were by definition not done under 22 those regulations. 23 Q. Well, the memo says what it 24 says, doesn't it, and leaves subject to Page 332 1 interpretation whether or not U.S. GLP 2 regulations were in effect in the early 70's, 3 doesn't it? 4 A. I'm sure that would be easily 5 documented one way or the other. 6 Q. But this memo, Exhibit 7, 7 doesn't say specifically that the U.S. GLP 8 regulations were not in effect in the early 9 1970's, does it? 10 A. That is correct. 11 (PLAINTIFFS' EXHIBIT 8 WAS 12 MARKED FOR IDENTIFICATION AND 13 RECEIVED IN EVIDENCE.) 14 Q. Can you identify Exhibit 8, 15 Doctor Fuller? 16 A. Yes, it appears to be an 17 E-mail message that I wrote to Leigh Thompson. 18 Q. All right. 19 A. That's in response to his 20 inquiry. 21 Q. That memo says, I think Ivan 22 was probably the first monitor assigned. Who is 23 Ivan? 24 A. Ivan Bennett. Page 333 1 Q. Then he goes on to say, then 2 Bob Shulman was hired in out of private practice 3 of psychiatry in Bar Harbor, Maine -- was hired 4 in out of private practice. I put the wrong 5 emphasis on it, didn't I? 6 A. Right. 7 Q. You go on to say, he had no 8 experience at all in drug research and spent his 9 time visiting psychiatric research centers, 10 getting advice about clinical studies and trying 11 to pick the best centers. That's what you said, 12 isn't it, Doctor? 13 A. Yes. 14 Q. Then you go on to say, that 15 went on nearly two years it seems to me, but 16 before he got any studies initiated, he resigned 17 and joined one of those centers. Is that what 18 happened, Doctor Fuller? 19 A. I think that's correct. 20 Q. Then it says, for a while 21 there, no clinical -- for a while there was no 22 clinical monitor assigned, doesn't it? 23 A. Yes. 24 Q. Then it says, I, meaning you, Page 334 1 volunteered out of desperation but was not hired, 2 correct? 3 A. That's correct. 4 Q. And then you say, Irv Slater, 5 this is the Doctor Slater we have been talking 6 about earlier, isn't it? 7 A. Yes. 8 Q. Was assigned for a short time 9 after he was removed as pharmacology director and 10 before he retired -- 11 A. Semicolon. 12 Q. Semicolon. That's what you 13 say there, correct? 14 A. Yes. 15 Q. Does this refresh your 16 recollection about Doctor Slater and his 17 involvement? 18 A. Yes. It clarifies the 19 question earlier about did Doctor Slater replace 20 Doctor Shulman. It was my recollection and this, 21 I think, verifies it that that was not an 22 immediate replacement, that there were actually a 23 period of time after Doctor Shulman left when 24 there was not a clinical monitor assigned, so Page 335 1 there was some gap there in between those two. 2 Q. Do you know why Doctor Slater 3 was removed as pharmacology director? 4 A. I could only speculate on 5 that. 6 MR. MYERS: Don't speculate, Doctor 7 Fuller. If you know, tell him, if you don't 8 know, tell him that, but don't speculate. 9 A. I do not know. 10 Q. Well, if you have a reasonable 11 judgment in that connection, you can certainly 12 give me that. 13 A. I imagine it was because his 14 superiors were not satisfied with his 15 administrative style. 16 Q. Did you have any problems with 17 Doctor Slater, yourself, his administrative 18 style? 19 A. No, I did not. 20 Q. He pretty well gave you a free 21 rein, didn't he? 22 A. You are referring back to an 23 earlier period when I actually reported to him? 24 Q. Yes, and when you were doing Page 336 1 your early research in this area. 2 A. When I was reporting to Doctor 3 Slater, that was during the first five years of 4 my employment at Lilly, I very much appreciated 5 his encouragement and advice and assistance, yes. 6 Q. Then you go on to say, he, 7 meaning Irv Slater, correct? 8 A. I'm not -- I'm not sure where 9 you are. 10 Q. Right after the semicolon. 11 A. Yes. 12 Q. He, when you say, he, you mean 13 Irv Slater, don't you? 14 A. Yes. 15 Q. He got a study going in post -- 16 A. Postanoxic intention 17 myoclonus. 18 Q. -- postanoxic intention 19 myoclonus, but only pilot studies in depression, 20 is that correct? 21 A. That's correct. 22 Q. Then you go on to say, Paul 23 Stark took over when Slater retired, I may have 24 left out a step or two, correct? Page 337 1 A. Correct. 2 Q. Is it your recollection that 3 all Doctor Slater did was get some pilot studies 4 done in depression? 5 A. As I testified earlier, I 6 believe the definitive results did not come in 7 until after Doctor Slater left. 8 Q. No, I'm not asking you when 9 the definitive results came in, I'm asking you 10 about what Doctor Slater did, Doctor Fuller, and 11 is it -- does this refresh your recollection that 12 all he did was pilot studies in depression? 13 A. The studies that he initiated 14 may have gone on to yield definitive results, I 15 frankly don't remember that for sure. But at the 16 time that Doctor Slater left, I think all that 17 had been completed were pilot studies. 18 Q. Well, you say he got a study 19 going on postanoxic intention myoclonus, but only 20 pilot studies in depression. The way I read 21 that, Doctor Fuller, you're saying that all that 22 Doctor Slater did was get a pilot study going in 23 depression, is that incorrect? 24 MR. MYERS: I object to the form, you Page 338 1 mischaracterized not only his testimony, but what 2 I think the thing says on it's face. 3 A. I think the -- you're reading 4 of the memo I think was correct. I think the -- 5 your interpretation may be slightly different 6 than what was intended. 7 Q. Well, you wrote it, tell me 8 what you intended. If what you said is -- if he 9 did more than the postanoxic intention myoclonus 10 study and if he did more in connection with 11 depression other than a pilot study in 12 depression, please tell us, Doctor. 13 A. I can tell you my recollection 14 of the situation now more reasonably than I can 15 tell you what I had in mind on the day I wrote 16 this E-mail message, partly because I don't know 17 what -- here it is, in December, 1982. As I 18 testified before, there had been a number of 19 clinical studies begun prior to the time that 20 Doctor Slater was assigned as clinical monitor 21 and there were, I imagine, additional studies 22 begun during the period of time that he was 23 clinical monitor. The nature of those studies 24 was what we call open label studies, which are Page 339 1 not double-blinded, meaning that the results are 2 not going to prove in a statistically 3 quantifiable way the efficacy of the drug. 4 Q. Let me stop you there if I 5 can, Doctor. 6 A. Sure. 7 Q. Then why do you do open label 8 studies, why are they done? 9 A. You do open label studies 10 partly to gain some experience with the drug, in 11 terms of what doses are going to be useful, what 12 kinds of side effects there might be that you 13 might encounter, what the nature of the response 14 is, how rapidly the response might be occurring 15 and other factors of that sort will then permit 16 you to design double-blind definitive studies in 17 the most appropriate way to get the most accurate 18 answer. 19 The completion of the 20 definitive studies, the double-blind clinical 21 studies and the analysis of the data that 22 resulted from them, occurred at a period of time 23 after Doctor Slater left. I could not remember 24 back that many years ago, the exact status of Page 340 1 each of those studies on the day that Doctor 2 Slater left, that's beyond my capability. 3 Q. But, in this message to Doctor 4 Thompson, you say he only did pilot studies in 5 depression. 6 A. The tone of the memo is that 7 the definitive studies were completed after 8 Doctor Slater left and while Doctor Stark was the 9 clinical monitor and that is correct. 10 Q. Simple, Doctor Fuller, do you 11 know whether or not Doctor Slater did anything in 12 connection with depression other than pilot 13 studies? 14 A. There's a difference between -- 15 doing can mean different things. It can mean 16 initiated or it can mean completed, for example. 17 I already testified that to the best of my 18 recollection those studies were not completed 19 while Doctor Slater was here. Were they 20 initiated while Doctor Slater was here, I think I 21 testified I don't remember. 22 Q. Who is Doctor Thompson to whom 23 this memo is addressed? 24 A. Doctor Thompson is a physician Page 341 1 at Lilly. 2 Q. What's his title, Doctor 3 Fuller? 4 A. I believe his current title is 5 chief scientific officer. 6 Q. Officer, is he an officer of 7 the corporation? 8 A. I think that's right, I don't 9 know. 10 Q. What was his title in December 11 of '92? 12 A. I do not know what his title 13 was. Doctor Thompson has been in the medical -- 14 came into the medical division of Lilly Research 15 Laboratories and has held a variety of positions 16 within the medical division and I do not know 17 what his title was in December of 1992. 18 Q. Why were you directing a memo 19 to Doctor Thompson concerning the history of 20 Prozac? 21 A. It appears to me that it was 22 in response to an inquiry from Doctor Thompson. 23 Q. Do you recall why he was 24 making inquiry to you? Page 342 1 A. I may not even have known why 2 he was making inquiry to me. 3 Q. What was Doctor Thompson's 4 relationship to Prozac, did he do any clinical 5 trials on Prozac? 6 A. No, I don't think. 7 Q. Was he a medical monitor on 8 Prozac? 9 A. No. 10 Q. Did he -- what was his 11 connection, as far as you understood it with 12 Prozac? 13 A. During a period of time, he 14 was the director or possibly called the 15 vice-president of the medical division where 16 Prozac was being monitored. 17 Q. Was he the senior official 18 overseeing the development of Prozac? 19 A. Doctor Thompson joined the 20 company sometime during the development of 21 Prozac, I don't remember what year that was. 22 Q. I didn't ask you when Doctor 23 Thompson joined the company, Doctor Fuller, I 24 asked you if he was the senior official Page 343 1 overseeing the development over Prozac. 2 MR. MYERS: He was trying to answer 3 your question, Mister Smith. You may not like 4 the way he answered it, but he was trying to 5 answer your question. 6 MR. SMITH: That's your 7 interpretation, Counsel. 8 MR. MYERS: That's right, it is. 9 A. I can say with confidence that 10 he was not the senior official during the early 11 development of Fluoxetine because he wasn't here 12 in 1972. 13 Q. Was he ever the senior 14 official overseeing Prozac? 15 A. As I would have said had I 16 been permitted to complete my sentence earlier, I 17 believe he became vice-president of the medical 18 division during the period of time before the 19 development of Prozac was completed and if I'm 20 correct in that recollection, then he would have 21 been the senior official in the chain of command 22 within the medical division at that time. 23 Q. Who would he have reported to, 24 let's say, at the time you directed this memo? Page 344 1 A. I could only guess at that, it 2 may have been Doctor Mel Perelman. 3 Q. President of Lilly research 4 labs at the time? 5 A. He was at that time, I 6 believe. 7 Q. Did you have anything to do, 8 Doctor Fuller, with the decision to make 9 Fluoxetine available recently in a ten milligram 10 pulvule? 11 A. No, I don't believe I did have 12 anything to do with that. 13 Q. In other words, it was 14 available in ten milligram concentrations, but 15 only orally up until February of last year, as I 16 recall, or this year, do you know anything about 17 that? 18 A. I'm aware that it recently 19 became available. 20 Q. Do you know why the decision 21 was made to make it available in ten milligram 22 quantities? 23 A. I imagine it was because it 24 was agreed there was a medical need for that Page 345 1 capsule strength. 2 Q. Do you know who would have 3 been involved in that decision? 4 A. I'm sure many of the senior 5 administrators within Lilly, certainly within the 6 Lilly Research Laboratories and particularly 7 within the medical component would have been 8 involved in that. 9 Q. Were you consulted in any 10 manner? 11 A. No, I don't recall that I was. 12 MR. SMITH: Let's take a lunch break. 13 (A LUNCH RECESS WAS TAKEN.) 14 Q. (BY MR. SMITH) Doctor Fuller, 15 is cocaine a serotonin reuptake inhibitor? 16 A. Among the many things that 17 cocaine does, one of them is to inhibit serotonin 18 uptake, although it isn't a very potent serotonin 19 uptake inhibitor. 20 Q. Can you answer that in a yes 21 or no fashion, is cocaine a serotonin reuptake 22 inhibitor? 23 MR. MYERS: Doctor Fuller, before you 24 answer, let me tell you, if the question is Page 346 1 capable of an answer yes or no, certainly do it, 2 but if you need to explain, then explain. 3 A. The answer is yes. 4 Q. Is Methadone a serotonin 5 reuptake inhibitor? 6 A. The answer there is that it 7 depends on the circumstances that you are 8 referring to. Would you tell me exactly what you 9 mean by that question? 10 Q. Where it's given to an 11 individual in a therapeutic mode. Does that 12 help? 13 A. Yes. I think it's very 14 unlikely that at therapeutic doses it's a 15 serotonin uptake inhibitor. 16 Q. Is it a serotonin uptake 17 inhibitor -- is Methadone a serotonin uptake 18 inhibitor in higher than therapeutic doses? 19 A. It probably would be. 20 MR. SMITH: No further questions. 21 * * * * * * * * * * 22 CROSS EXAMINATION 23 BY MS. ZETTLER: 24 Q. Doctor Fuller, have you given Page 347 1 any other depositions in any other cases related 2 to Fluoxetine? 3 A. Yes. 4 Q. How many? 5 A. Two, I believe. 6 Q. Do you remember what the names 7 of those cases were? 8 A. No, I have no idea. 9 Q. When did you give the first 10 deposition that you gave in regards to 11 Fluoxetine? 12 A. It probably was -- I don't 13 remember, I think it's shortly after the Los 14 Angeles riots, if that helps. 15 Q. Why does that milestone stick 16 out in your head? 17 A. Because it was in Los Angeles. 18 Q. How long did that deposition 19 last? 20 A. Less than one day. 21 Q. How about the second one, how 22 long after the L.A. dep did you give that dep? 23 A. It was probably a year ago. 24 Q. And where was that dep taken? Page 348 1 A. In Indianapolis. 2 Q. How long did that deposition 3 last? 4 A. It was probably a few hours. 5 Q. Did those lawsuits involve 6 claims by people for injuries due to adverse 7 reactions, such as suicide or violent aggressive 8 behavior, anything of that nature? 9 A. To be honest, I don't remember 10 the nature of the claims at this point. 11 Q. Did you review any documents 12 or given any documents to be reviewed before 13 either one of those depositions that related 14 specifically to the claims being made by the 15 plaintiffs, as opposed to your -- just 16 exclusively on your work with Fluoxetine? 17 A. Not to the best of my 18 recollection. 19 Q. Have you ever heard of Joseph 20 Wesbecker? 21 A. I've heard of someone named 22 Wesbecker, I don't remember his first name. 23 Q. How did you hear of this 24 Wesbecker person? Page 349 1 A. The person I'm thinking about, 2 I read about in the newspapers. 3 Q. What did you read about Mister 4 Wesbecker in the newspapers? 5 A. That he killed some people and 6 himself, I believe. 7 Q. Have you discussed Mister 8 Wesbecker's actions with anybody at Eli Lilly? 9 A. In all probability, I have, 10 but I don't remember specific discussions. 11 Q. Why do you say in all 12 probability you have? 13 A. Because I am aware that there 14 was a lot of publicity surrounding the case which 15 had to do with Fluoxetine. 16 Q. Have you, in your capacity as 17 a biochemist at Lilly, been asked by anybody at 18 Lilly to do animal studies that may be relevant 19 to the issue of whether or not Fluoxetine causes 20 people to become violent-aggressive? 21 A. I have not been asked by 22 anyone to do such animal studies, no. 23 Q. Have you done such studies? 24 A. No, I think none of the Page 350 1 studies that I have done would pertain 2 specifically to aggression. 3 Q. Have you used any of the 4 studies that you've done in response to inquiries 5 either by a governmental agency such as the FDA 6 or somebody at Lilly with regards to the subject 7 of violent-aggressive behavior and the use of 8 Fluoxetine? 9 MR. MYERS: Object to the form. Used 10 them for what? 11 MS. ZETTLER: Like as either an 12 informational piece or in support of a theory 13 that was positive by somebody at Lilly. 14 A. As best I understand your 15 question, the answer is no. 16 Q. Are you aware of any studies, 17 animal studies whatsoever, that were done at 18 Lilly specifically to research whether or not 19 there was a connection between the use of 20 Fluoxetine and violent-aggressive behavior? 21 A. Are you asking a connection 22 between Fluoxetine and violent-aggressive 23 behavior in people? 24 Q. We can start with rats or Page 351 1 animals first. 2 A. There were studies on 3 Fluoxetine done at Lilly that showed that it 4 reduced aggressive behavior in rats. 5 Q. And were those studies 6 conducted specifically to study that phenomena, 7 or was that something that came up as a 8 peripheral in another study? 9 A. No. They were studies that 10 were done specifically to investigate the effect 11 on muricidal aggression. 12 Q. Who conducted those studies? 13 A. Doctor Paul Stark. 14 Q. Do you know how many studies 15 Doctor Stark conducted? 16 A. Well, there were -- no, I 17 don't know about the number of separate studies. 18 Basically, there was -- there were studies 19 showing a dose dependent suppression of muricidal 20 aggression in rats treated with Fluoxetine. 21 Q. So, a dose dependent what? 22 A. Suppression of aggressive 23 behavior. 24 Q. The greater the dose, the more Page 352 1 the behavior was suppressed? 2 A. Yes, up until a maximum 3 suppression of course. 4 Q. What would constitute maximum 5 suppression? 6 A. No aggression. 7 Q. Okay. 8 Q. Are you aware of any other 9 studies that Doctor Stark did on researching 10 aggressive behavior in rats as it related to the 11 use of Fluoxetine? 12 A. No. 13 Q. Do you recall what the highest 14 dose of Fluoxetine administered to the rats by 15 Doctor Stark was? 16 A. No, I don't. 17 Q. Were those doses that were 18 administered to the rats by Doctor Stark, were 19 they meant to be comparable to doses in humans? 20 A. They were chosen to be doses 21 that were known to inhibit serotonin uptake in 22 rats. 23 Q. Did every dose administered to 24 the rats produce a suppression of aggression? Page 353 1 A. I don't remember the answer to 2 that. The lowest doses may have been 3 insufficient, that would be a typical experiment, 4 but I don't remember specifically about this one. 5 Q. Do you know if all of the 6 rats' aggressions were suppressed? 7 A. Again, that would depend upon 8 the dose of Fluoxetine, the bigger the dose, the 9 more the suppression, and I couldn't give you the 10 numbers for individual groups of rats. 11 Q. Okay. Was this study 12 published? 13 A. Yes, it was. 14 Q. Do you know when it was 15 published? 16 A. It was published in, I 17 believe, the British Journal of Psychiatry in a 18 paper authored by Stark, Wong and myself, I 19 believe. 20 Q. British Journal of Psychiatry? 21 A. I believe that was the name of 22 the journal. 23 Q. It wasn't the British Medical 24 Journal, was it? Page 354 1 A. No, I don't think so. 2 Q. So, it was Doctor Stark, 3 Doctor Wong and yourself that were the authors? 4 A. Yes, I think so, maybe not in 5 that order. 6 Q. Okay. Did you participate in 7 the study? 8 A. Not to a substantial degree, 9 the -- probably in terms of advising about the 10 choice of doses, for example. The publication 11 was broader than that study, that was one of the 12 studies included in the publication. 13 Q. Do you recall what the title 14 of the publication was, not the journal, but the 15 article itself? 16 A. No, I'm sorry, I don't. It 17 certainly had the word Fluoxetine in the title. 18 Q. Do you remember when it was 19 published, approximately? 20 A. My guess would be about 1985. 21 Q. Why was Doctor Stark studying 22 the suppression of aggressive behavior in rats in 23 the 1980's? 24 A. He actually wasn't studying in Page 355 1 the 1980's, the data were obtained prior to that 2 time. The data were obtained back in the 1970's 3 when Fluoxetine -- when most of the animal 4 studies on Fluoxetine were conducted and the -- 5 that test was actually one that is sometimes used 6 in the characterization of antidepressant drugs, 7 and so that was a test that Doctor Stark was 8 using in his laboratory at that time. 9 Q. Was this done before or after 10 the majority of your studies were done, or 11 during? 12 MR. MYERS: When you say his studies, 13 which ones? 14 Q. Well, the bulk of of your 15 studies before the human trials began. In other 16 words, let me ask it this way: Was this study 17 done as a result of some behavior or something 18 else that you were observing in other animal 19 tests that were being run at Lilly on Fluoxetine? 20 A. No, it was simply one of the 21 tests that a lot of drugs at Lilly were put 22 through at that time. 23 Q. Any other tests besides Doctor 24 Stark's rat test in aggression suppression that Page 356 1 you recall related to the issue of aggressive 2 behavior in rats or other animals? 3 A. Are you asking about studies 4 done at Lilly? 5 Q. Right. 6 A. No, none that I recall. 7 Q. Earlier we talked a little bit 8 about food intake suppression? 9 A. Yes. 10 Q. With, I believe it was cat or 11 rats? 12 A. I believe what we were 13 discussing were studies in rats. 14 Q. And then we also talked about 15 reduction in REM sleep in rats and cats, right? 16 A. Yes. 17 Q. Any other behavioral changes 18 that you observed in the laboratory animals you 19 were testing on Fluoxetine? 20 MR. MYERS: You mean the tests -- 21 these are the tests that he did now? 22 MS. ZETTLER: Right. 23 A. Well, I didn't do, of course, 24 the studies on REM sleep. I didn't do most of Page 357 1 the studies on food intake. Most of the studies 2 on food intake were done by others. As I 3 testified yesterday, the studies that we have 4 done with Fluoxetine in rats, have been largely, 5 and mice, have been largely neurochemical ones 6 that address the ability of the compound to block 7 serotonin uptake and to not block the uptake of 8 other monoamines, and as I testified yesterday, 9 in those studies in rats and mice, we routinely 10 observe the animals to see if there is any 11 visible behavioral changes and we did not see any 12 in rats or mice. 13 Q. Did you see any anorexic 14 behavior? 15 A. We wouldn't see anorexic 16 behavior in these kinds of experiments because 17 the animals do most of their eating at night. So 18 during the period of time that we were working 19 with them, you wouldn't expect to observe them 20 eating very much, so you wouldn't see anorexic 21 activity in those kinds of experiments. 22 Q. Did you routinely weigh the 23 animals? 24 A. Yes, but most of the studies Page 358 1 that we did were single dose studies with 2 Fluoxetine, so that the animals were killed for 3 neurochemical measurements after a single dose, 4 so that there would not -- you would not observe 5 a change in body weight as a consequence of the 6 drug. 7 Q. My question is, I understand 8 that you didn't do your tests and you weren't 9 looking at before behavioral changes, my question 10 is during the studies, did you notice any overt 11 behavioral changes on the rats that were on 12 Fluoxetine, regardless of how long they were on 13 it? 14 A. My answer is still no. 15 Q. Okay. Are you aware of any 16 behavioral studies that were done at Lilly that 17 demonstrated overt behavioral changes of animals 18 on Fluoxetine? 19 A. No, I think -- well, are you 20 asking other than what we have talked about 21 already or -- 22 Q. Yes. I mean I'm just 23 interested to know if there were behavioral 24 changes that were noticed during the behavioral Page 359 1 studies that either weren't anticipated or 2 weren't being studied for? 3 A. None that I recall. 4 Q. How about hyperirritability in 5 rats? 6 A. I don't remember any such 7 effects. 8 (PLAINTIFFS' EXHIBIT 9 WAS 9 MARKED FOR IDENTIFICATION AND 10 RECEIVED IN EVIDENCE.) 11 Q. Go ahead and take a look at 12 Exhibit 9, Doctor. 13 A. Yes, I see it. 14 Q. Do you recognize Exhibit 9? 15 A. It is a project team minutes, 16 in which the word team is mistyped, written in 17 1974. 18 Q. And you were the author of 19 this? 20 A. Yes. Typist as well, 21 probably. 22 Q. So, we can blame you for the 23 typos, huh? The second paragraph on the first 24 page talks about a ninety day toxicity study in Page 360 1 rats? 2 A. Yes. 3 Q. Are you familiar with that 4 study? 5 A. Familiar with it would 6 certainly be an exaggeration. I'm aware it was 7 done, yes. 8 Q. Do you know who performed that 9 study? 10 A. It would have been done in the 11 toxicology division at Greenfield and Doctor John 12 Wold was the toxicologist representative on the 13 project team, although the study was not 14 necessarily done in his personal laboratory. 15 Q. Did Doctor Wold report the 16 results of this study, or at least the status of 17 this study, as of the date of this project team 18 meeting? 19 A. Yes. 20 Q. And he reported that there was 21 a pronounced hyperirritability in rats, at least 22 the class of rats that were included in the 23 study, correct? 24 A. Yes. Page 361 1 Q. It also states that all of the 2 rats in the high dose study had died at that 3 point, correct? 4 A. Yes. 5 Q. The next lower dose were 6 eating well and gaining weight, correct? 7 A. Yes. 8 Q. And after that came the group 9 that showed hyperirritability, correct -- oh, no, 10 I take that back, I'm sorry. The ones that were 11 gaining weight and eating were exhibiting 12 hyperirritability, correct? 13 A. The rats at the point oh three 14 percent in the diet dose are the ones, I believe, 15 that are referred to here as showing the 16 pronounced hyperirritability, yes. 17 Q. In your recitation of the 18 minutes, you state that the group of rats that 19 were suffering from hyperirritability, at least 20 the behavior was observed during the second to 21 the fourth weeks that had been disappearing, 22 correct? 23 A. Yes. 24 Q. What did that indicate to you Page 362 1 as a biochemist? 2 A. I think the interpretation was 3 primarily in the hands of the toxicologists. It 4 didn't indicate anything particular to me, I 5 don't believe. 6 Q. Do you have an explanation, 7 whatsoever, why this particular group of rats 8 would start exhibiting a pronounced 9 hyperirritability for a period of time? 10 A. No. I would guess that it 11 might be related to their decreased food intake 12 however. 13 Q. How would that make them 14 become hyperirritable? 15 A. When rats are deprived of food 16 that can happen. 17 Q. Are you saying that these rats 18 were purposely deprived of food? 19 A. No, I'm saying they were not 20 eating as much as the control rats were. 21 Q. And when we're talking about 22 this group of rats, we're talking about rats that 23 were on Fluoxetine, correct? 24 A. That's correct. Page 363 1 Q. Is it your recollection that 2 this group of rats initially was not eating -- 3 were not eating? 4 A. I believe there was a 5 decreased amount of eating, not that they were 6 not eating. 7 Q. Do you know if there is a 8 correlation between their eating less and their 9 hyperirritability, as far as a timewise? 10 A. They were both occurring at 11 the same time, I presume, is that the question? 12 Q. Yes, right. 13 A. I assume they were both 14 occurring at the same time. 15 Q. Is it your understanding or 16 recollection that once they started eating again 17 that the hyperirritability went away? 18 A. I think that's a plausible 19 explanation for the results. Again, I don't have 20 a recollection of the -- this study twenty years 21 ago. 22 Q. Could it be that they started 23 eating because the hyperirritability was 24 disappearing? Page 364 1 A. I would -- I guess I would not 2 expect that kind of relationship, but -- no. 3 Q. Do you relate their decrease 4 in eating to the administration of Fluoxetine? 5 A. I would imagine that is the 6 cause, since in all other respects they would 7 have been like the controlled rats. 8 Q. Do you relate their 9 hyperirritability to the administration of 10 Fluoxetine? 11 A. For the same reason, I would 12 expect that it was a consequence of the 13 administration of Fluoxetine, again, as I said, 14 probably -- possibly related to their decrease in 15 food intake. 16 Q. Was this study published? 17 A. I do not know. 18 Q. Who would know that? 19 A. I'm sure John Wold would know 20 that. 21 Q. Is Doctor Wold still with 22 Lilly? 23 A. Yes. 24 Q. And where is he located within Page 365 1 the corporate structure now? 2 A. I don't remember. He's still 3 in Lilly Research Laboratories, but I don't 4 remember his exact title. 5 Q. Is he here in Indianapolis? 6 A. Yes. 7 Q. Any other toxicology studies 8 with animals, that you recall, where behavior 9 that you relate to Fluoxetine was observed? 10 A. Not that I recall, again, 11 pointing out that I was not involved in the 12 toxicologic studies. 13 Q. You were chairman of the 14 project team during this period of time, right? 15 A. Yes. 16 Q. Would the toxicologist doing 17 studies on Fluoxetine generally report to you? 18 A. They would report the studies 19 to the project team, they didn't report to me 20 administratively. 21 Q. Would all studies that were 22 being conducted be reported? 23 A. I think so, yes. 24 Q. So, if there were other Page 366 1 studies out there, you would have, at least at 2 one point, been made aware of them? 3 A. Yes. 4 Q. Do you recall a dog study 5 where the dogs became aggressive or at least some 6 of the dogs became aggressive? 7 A. No, I don't. 8 (PLAINTIFFS' EXHIBIT 10 WAS 9 MARKED FOR IDENTIFICATION AND 10 RECEIVED IN EVIDENCE.) 11 Q. Have you had a chance to 12 review Exhibit 10? 13 MR. MYERS: I just gave it to him. 14 MS. ZETTLER: I'm sorry. 15 A. I glanced through it. 16 Q. Do you recognize this exhibit? 17 A. It appears to be a memorandum 18 from Greg Brophy dated May 12th, 1981. 19 Q. Do you recall seeing this 20 memorandum before today? 21 A. I'm sure I did. Do I 22 specifically recall it, nothing rings a bell 23 right now. 24 Q. Do you recall the study that Page 367 1 Greg Brophy is talking about in this memo? 2 A. This was a one year dog study, 3 and yes, I am aware that a one year dog study was 4 done. 5 Q. Do you recall that, as he says 6 at the bottom of the first page, a total of six 7 dogs from the high dose group were removed from 8 treatment for periods of one to seventeen days 9 due to severe occurrences of either aggressive 10 behavior, ataxia, or anorexia? 11 A. I didn't recall that prior to 12 reading that sentence, no. 13 Q. Do you recall that in the 14 preceding ninety day dog study similar CNS toxic 15 signs were seen? 16 A. I did not recall that 17 independently of this memo, no. 18 Q. Do you have an opinion what 19 caused six of the dogs in this study to become 20 aggressive, suffer from ataxia or anorexia? 21 A. Well, these are obviously 22 toxic doses and these are simply signs of that 23 toxicity. I have no explanation in any sort of 24 specific terms for any of the toxic signs. Page 368 1 Q. Were all of these dogs who 2 exhibited these effects of aggressive behavior, 3 ataxia or anorexia on the same dosage, to your 4 knowledge? 5 A. Were they on the same dose? 6 Q. Right, in the one year dog 7 study. 8 A. I could only try to ascertain 9 that by careful reading of this document. Would 10 you like me to do that? 11 Q. Sure. 12 A. Well, the sentence says that 13 the six dogs that were removed from treatment 14 because of these occurrences were all in the high 15 dose group as a matter of fact, yes. 16 Q. So, that would have been the 17 same group, same dosage across the board? 18 A. Yes. 19 Q. It also says in the preceding 20 ninety day dog study, at five, ten and twenty 21 milligrams per kilogram, those dogs exhibited 22 similar toxic signs? 23 A. Yes, it does. 24 Q. Are five, ten and twenty Page 369 1 milligrams per kilogram in dogs considered a high 2 dose? 3 A. Yes, they are. 4 Q. All three of them? 5 A. Yes. 6 Q. What would be a dose in dogs 7 that would produce a serotonin reuptake 8 inhibition? 9 A. There have been limited 10 studies to that effect in dogs. One way in which 11 we attempted to measure that was by -- and the 12 reason for the limited study is, of course, one 13 does not like to sacrifice dogs, and that's the 14 only way to get neurochemical measurements in the 15 brain. But we did a number of studies in dogs 16 looking at blood platelets in which we measured 17 the serotonin content of blood platelets, which 18 is an indication of the extent of inhibition of 19 uptake. Blood platelets have a serotonin uptake 20 carrier that is identical to the uptake carrier 21 in the brain. So, blood platelets are an 22 accessible tissue that one can measure without 23 having to kill the animals. And, we generated a 24 substantial amount of data on blood platelet Page 370 1 serotonin, I think probably in this particular 2 study. But, I do not recall the details of those 3 results in terms of what, for example, a minimum 4 effective dose might be. 5 Q. Okay. So you don't know or 6 you don't recall at this time what a minimum 7 effective dose, as far as blocking uptake of 8 serotonin, in dogs would be? 9 A. That's correct. 10 Q. Was the issue of agitation in 11 humans using Fluoxetine raised prior to 1990, to 12 your knowledge, at Eli Lilly? 13 A. I don't have any specific 14 recollection of that. The discussion would most 15 likely have been within the medical division and 16 I might not have participated, but there might 17 have been, in the discussion of clinical results, 18 that might well have been mentioned along with 19 any other side effects that were observed. 20 Q. How about in the early human 21 trials, were any adverse reactions such as 22 agitation seen in humans -- normal humans given 23 the drug? 24 A. That's what I was referring Page 371 1 to. I don't have specific recollection of the 2 listing of side effects and their frequency, but 3 certainly in the discussion of all of the 4 clinical studies that were done, there was 5 careful attention paid to side effects, as well 6 as efficacy and those were tabulated and analyzed 7 and discussed. 8 Q. Do you have any recollection 9 of patients converting to depression from 10 agitation? 11 A. I don't have any specific 12 recollection of that. Again, those were items 13 that would have been discussed principally within 14 the medical division and I might well have heard 15 some of those discussions, but as far as 16 specifically remembering them right now, I don't. 17 Q. Do you recall the decision -- 18 a decision being made to allow the use of 19 benzodiazepines for agitation in clinical trials? 20 A. I believe I do remember that. 21 Q. I'm sorry your answer was you 22 do recall that? 23 A. I think I do. 24 Q. When was that decision made? Page 372 1 A. I couldn't tell you that. 2 Q. Do you know what prompted that 3 decision? 4 A. I imagine it was the clinical 5 investigators who were doing the studies felt it 6 was a good idea, because one of the reasons for 7 that would be that, unlike the trycyclic 8 antidepressant drugs, many of which are sedating, 9 probably because of their interaction with 10 neurotransmitter receptors as we talked about 11 yesterday. Since Fluoxetine does not interact 12 with those receptors and therefore does not have 13 that specific action, then in patients in whom 14 that type of agitation was found, it might need a 15 separate drug to treat. 16 Q. Are you saying that, in your 17 opinion, Fluoxetine has a stimulant property to 18 it as opposed to sedating properties? 19 MR. MYERS: I object to the form, I 20 don't know that he used that term. 21 MR. SMITH: That's why she is asking 22 him that. 23 MS. ZETTLER: Right. 24 MR. SMITH: Because he didn't use the Page 373 1 term. 2 MR. MYERS: Thank you for that side 3 bar comment. 4 A. I did not use the term 5 stimulant in my statement, what I said was that 6 Fluoxetine does not exert a sedating effect as 7 many of the tricyclic antidepressant drugs do. 8 Q. And my question is, does 9 Fluoxetine exert a stimulating effect? 10 A. In general, the answer is no. 11 In animals such an effect is not seen, and in 12 humans it typically is not seen. I think there 13 are a few individuals who show an effect which 14 has been described as nervousness, which is not 15 generally described as a stimulant effect, but 16 someone might use that term, I think I would not. 17 Q. Are you saying these are 18 people on Fluoxetine? 19 A. Yes. 20 Q. Is that connection between the 21 use of Fluoxetine and the nervousness that you 22 talked about been made in those people on 23 Fluoxetine? In other words, you said a small 24 percentage of people seem to exhibit something Page 374 1 that could be termed as nervousness while on 2 Fluoxetine, correct? 3 A. I believe that is one of the 4 side effects that is reported in the package 5 literature. 6 Q. Was the use of benzodiazepine 7 allowed to counteract this effect of Fluoxetine 8 in the clinical trials? 9 A. I think in those protocols, 10 where it was allowed, it was allowed for the 11 purpose of treating that condition if it occurred 12 independently of whether it was believed to be 13 caused by Fluoxetine or not. 14 Q. So, if somebody became nervous 15 on a placebo, they would be given benzodiazepine? 16 A. I believe so. 17 Q. Do you know how many people on 18 placebo became nervous to the point where they 19 had to be administered benzodiazepine? 20 A. No, I have no idea. 21 Q. Do you know how often 22 benzodiazepine was administered to study patients 23 taking Fluoxetine? 24 A. No, that is not the type of Page 375 1 information I would have. 2 (PLAINTIFFS' EXHIBIT 11 WAS 3 MARKED FOR IDENTIFICATION AND 4 RECEIVED IN EVIDENCE.) 5 Q. Before you read that, Doctor, 6 is there a difference in your mind between a 7 person who is agitated and a person who is 8 nervous? 9 A. I would think there is a 10 reason for those two separate words, yes. 11 Q. Okay. What is your definition 12 of somebody who is suffering from agitation? 13 A. I would imagine that would 14 mean a person who was irritated, probably 15 restless. 16 Q. Anything else? 17 A. No. 18 Q. How about somebody who was 19 nervous? 20 A. I would imagine the chief 21 difference would be the irritation would not be 22 present. 23 Q. Okay. I'm sorry, go ahead and 24 look at Number 11. Page 376 1 MR. SMITH: While he's looking at that 2 while we're still on the record, I noticed this 3 morning that Ms. Huff had a tape recorder going 4 and she may have it going now. Obviously, it's 5 certainly her privilege to record anything she 6 wants, as far as I'm concerned. I had a call 7 from Mister Lore in connection with difficulty in 8 getting Doctor Slater to make his corrections and 9 to sign his deposition, as I understand it. And 10 I'm wondering if there is a position on the part 11 of Lilly that we are not getting an accurate 12 transcript or there is some problems with the 13 transcript that would require a separate 14 recording of the proceedings? 15 MR. MYERS: My understanding is that 16 Ms. Huff has made such recordings from time to 17 time for her own purposes, for note keeping and 18 related purposes. I'm not aware of any 19 significant transcription problems other than the 20 ones you typically get with lots of scientific 21 terms that come up in these depositions, so 22 that's my understanding. 23 MR. SMITH: That's fine. 24 MR. MYERS: I don't think one has to Page 377 1 do with the other. 2 Q. Doctor, did you review anybody 3 else's deposition transcript before today's 4 deposition or yesterday's deposition? 5 A. No, I don't believe so. 6 Q. Were you given any audio tapes 7 to listen to of other depositions? 8 A. No. 9 Q. Okay. Have you had a chance 10 to review Exhibit 11? 11 A. Yes. 12 Q. First paragraph on the first 13 page under the Phase 2 clinical study section, do 14 you see that? 15 A. Yes. 16 Q. Before we go into that, let me 17 digress a little bit, do you recognize this 18 Exhibit? 19 A. It's a set of project team 20 minutes from July 23rd, 1979. 21 Q. And you authored those 22 minutes? 23 A. Yes. 24 Q. On the first page, first full Page 378 1 paragraph under the heading, Phase 2 Clinical 2 Studies and Mental Depression, towards the middle 3 of the paragraph it says, some patients have 4 converted from severe depression to agitation 5 within a few days. In one case the agitation was 6 marked and the patient had to be taken off the 7 drug. Do you see that? 8 A. Yes. 9 Q. That doesn't mention 10 nervousness anywhere, right? 11 A. That's right. 12 Q. After that it says, the last 13 paragraph, in future studies the use of 14 benzodiazepines to control agitation will be 15 permitted. Do you see that? 16 A. Yes. 17 Q. Does that refresh your 18 recollection as to why the benzodiazepines were 19 allowed to be used in the clinical trials? 20 A. Yes. 21 Q. Why? 22 A. Well, this use was to control 23 the agitation, I'm not sure that applies 24 necessarily to all the clinical trials, but at Page 379 1 least the ones referred to here. 2 Q. So at least as of July of 3 1979, it was decided by the team that 4 benzodiazepines could be used in the clinical 5 trials for agitation? 6 A. The decision, that decision 7 would not be made by the project team, that would 8 be made within the medical division. It was 9 reported to the project team. 10 Q. That decision to do that was 11 reported to you as of July, 1979? 12 A. Yes. 13 Q. You don't know whether or not 14 the reason for administering benzodiazepines 15 changed at any period of time, correct? 16 A. That is correct. 17 Q. Or whether or not the use of 18 benzodiazepines was actually stopped at any point 19 in time, correct? 20 A. I don't know that, that's 21 correct. 22 Q. Phase 2 clinical studies, were 23 these still the open label studies that you were 24 talking with Paul about earlier? Page 380 1 A. It's impossible to say from 2 this. Phase 2 clinical studies would have 3 included the open label studies, but they also 4 included the, well, the double-blind studies. 5 But, as I read further in this document it 6 becomes clear, the third paragraph says all 7 studies up to now have been open label studies 8 and plans are in progress for double-blind 9 controlled studies comparing Fluoxedine to 10 placebo, Imipramine or Amitriptlyline. 11 Q. Does this refresh your 12 recollection as to whether or not the use of 13 benzodiazepines to control agitation was going to 14 be permitted in the double-blind controlled 15 studies, as well as any other open label studies 16 that were going to be done? 17 A. I would infer from what is 18 written here that that would be the case. 19 Q. Did anybody at Lilly have any 20 concern that the use of benzodiazepines might be 21 masking a side effect profile of the drug? 22 MR. MYERS: At this point in time? 23 MS. ZETTLER: Yes. 24 A. I could not answer that Page 381 1 question. I don't know what in all people at 2 Lilly might have thought. 3 Q. How about you, were you 4 concerned that it might have masked the side 5 effect profile of the drug? 6 A. I don't remember discussing 7 the issue in the project team, it's the sort of 8 issue that would have been discussed within the 9 medical division. 10 Q. Do you have an opinion now, 11 whether or not giving benzodiazepines to people 12 who became agitated on Fluoxetine would in effect 13 mask a side effect profile of Fluoxetine? 14 MR. MYERS: I object to the form, only 15 to the extent that is probably clearly a medical 16 question. But if you have some knowledge, 17 Doctor, certainly tell her. 18 A. Well, my knowledge is fairly 19 general as a noncommission, but as a 20 pharmacologist who has some knowledge of 21 psychopharmacology, I think the likelihood of 22 there being a masking is unlikely, because the 23 use of benzodiazepines would certainly be 24 recorded, so if there was an increased use of Page 382 1 benzodiazepines in this group, there would be a 2 record of that. 3 Q. Isn't the fact that the 4 agitation was being experienced by some people 5 that were given Fluoxetine, at least in the open 6 label studies, an indication that some people 7 were having an adverse reaction to the drug? 8 MR. MYERS: Same objection as to 9 nature of the question is medical, but if you 10 know tell her. 11 A. Well, in the sense that open 12 label studies are not conclusive with regard to 13 side effects any more than they are conclusive 14 with regard to efficacy. Certainly all side 15 effects are noted in open label studies, but 16 unless -- if they are side effects that commonly 17 occur in the population of patients, that is 18 depressed patients, then there would be no way of 19 knowing for sure whether they were induced by the 20 drug or not. And that sort of information, like 21 the efficacy data, would come most conclusively 22 from the controlled double-blind studies which 23 were done later. 24 Q. Do people suffering from Page 383 1 depression usually become agitated? 2 A. I think that is a not uncommon 3 feature associated with depression. 4 Q. Are you familiar with the 5 belief, in the psychiatric community, that 6 Fluoxetine produces jitteriness in some people? 7 MR. MYERS: Before he answers, let me 8 object to the form. I don't know that it's been 9 established by anybody that there is such a 10 belief in the psychiatric community. I don't 11 know what you mean by a belief. 12 Q. Can you answer my question, 13 Doctor? 14 MR. MYERS: If you can answer it, 15 certainly tell her. 16 A. I think in the list of side 17 effects associated with Fluoxetine use in the 18 package literature, for example, I don't believe 19 the term jitteriness is used probably, but the -- 20 perhaps a term like nervousness is used, by which 21 I would guess you mean about the same thing, so 22 I'm aware of that, yes. 23 Q. Are you aware that at least 24 one psychiatrist that has worked with Lilly has Page 384 1 recommended that in people who pose a serious 2 suicidal risk concomitant sedatives or 3 benzodiazepines be given to people on Fluoxetine? 4 MR. MYERS: I object to the form. If 5 you know, tell her. 6 A. I'm sorry, could you repeat it 7 again? I'm not sure I followed the last part of 8 that. 9 MS. ZETTLER: Why don't you read it 10 back. 11 (THE COURT REPORTER READ BACK THE 12 REQUESTED TESTIMONY.) 13 A. I'm not aware of what you 14 might have in mind there by a particular 15 psychiatrist. I'm not surprised that a 16 psychiatrist who felt that such drugs when needed 17 would recommend their use. 18 Q. In a particular type of 19 patients? 20 A. Correct, whatever he felt the 21 need or felt that such a drug would be 22 beneficial, I think he would recommend its usage. 23 Q. I'm sorry, are you done? 24 A. Yes. Page 385 1 Q. Are you surprised that there 2 would be a school of thought that in people who 3 were suffering from anxieties or otherwise 4 presented a serious suicide risk would require 5 the coadministration of a sedative while taking 6 Fluoxetine? 7 MR. MYERS: Object to the form and the 8 vague term, school of thought, as being awfully 9 vague and undefined. But if you know, tell her. 10 A. I guess, I don't -- I have 11 trouble answering the question for the same 12 reason, it isn't clear to me exactly what you 13 mean. 14 Q. Are you aware that there are 15 other governmental entities besides the FDA out 16 there that require or suggest that a sedative be 17 given to patients on Fluoxetine who are thought 18 to pose a suicidal risk? 19 MR. MYERS: Same objection. 20 MR. HARRIS: I'm going to object to 21 the form of that question. This man is not a 22 medical doctor and I think you are asking a 23 question about the prescribing of medication, so 24 in that sense I'm going to object that there is Page 386 1 no proper predicate and this witness is not 2 qualified to testify to the effect. 3 Q. Doctor, you're a 4 pharmacologist, correct? 5 A. Yes. No, I'm not aware of a 6 specific governmental agency that you referred 7 to. 8 Q. Have you ever heard of the 9 BGA? 10 A. Is the BGA a German regulatory 11 agency? 12 Q. Yes. 13 A. Yes, I have. 14 Q. Do you know anybody who works 15 for the BGA or with the BGA, outside of Lilly? 16 MR. MYERS: You mean somebody that's 17 employed by the BGA? 18 MS. ZETTLER: Or consults with them or 19 works with them on a regular basis outside of 20 Lilly. 21 A. I don't know that I do, it's 22 certainly possible that among the acquaintances 23 that I have someone of them consults with the 24 BGA, I might not even be aware of that. Page 387 1 Q. Do you have acquaintances in 2 Germany? 3 A. Yes. 4 Q. How many, outside of Lilly? 5 A. I don't know, I'm sure it 6 would be less than a hundred. 7 Q. Do any of your acquaintances 8 in Germany work for the BGA? 9 A. I think that's what I just 10 said, not to my knowledge. But among the 11 acquaintances that I have, are some 12 psychiatrists, for example, and it could well be 13 that one of them work for the BGA and I'm not 14 aware of that. 15 Q. To your knowledge, does the 16 BGA have an advisory committee type like we have 17 here at the FDA? 18 A. I do not know. 19 MS. ZETTLER: Do you want to take a 20 break? 21 (A SHORT RECESS WAS TAKEN.) 22 (PLAINTIFFS' EXHIBIT 12 WAS 23 MARKED FOR IDENTIFICATION AND 24 RECEIVED IN EVIDENCE.) Page 388 1 2 Q. A real quick question about 3 Exhibit 12, Doctor. You authored that paper or 4 are of the authors on that paper? 5 A. This is a report to the Food 6 and Drug Administration dated August, 1974, and 7 yes, I did. 8 Q. Was that paper or any form of 9 that paper published in a psychiatric medical or 10 scientific journal? 11 A. This was not published, I 12 think the findings may have been. The data may 13 have been published in a separate -- the finding -- 14 let me say it this way, the finding that 15 Fluoxetine inhibits amphetamine metabolism has 16 been published. 17 Q. Do you recall where? 18 A. There was a paper that I 19 coauthored with a group at the University of 20 Chicago and one of -- I think the first author 21 was George Ricaurte. 22 Q. Spell that, please? 23 A. R-I-C-A-U-R-T-E. 24 Q. Okay. Page 389 1 A. And it may have been published 2 in Neuropharmacology, but I'm not certain about 3 that. 4 Q. If you could go back to 5 Exhibit 11. Again, the first paragraph on the 6 first page, it talks about clinical studies in 7 mental depression proceeding under modified 8 protocols use higher doses of Fluoxetine, do you 9 see that? 10 A. Yes. 11 Q. Do you know why it was decided 12 to use higher doses of Fluoxetine at that time? 13 A. No, I do not have specific 14 knowledge of the reason for that. Doses up to 15 sixty milligrams and even higher had previously 16 been given in Phase 1 studies, for example, but 17 apparently from what I read here, these specific 18 protocols for these studies had not included 19 higher doses and it's apparent that someone, 20 possibly the investigators, felt that that would 21 be important to do. 22 Q. Does this Exhibit indicate to 23 you that a connection was being made between the 24 use of Fluoxetine and the occurrence of agitation Page 390 1 in some Fluoxetine patients? 2 MR. MYERS: Let me object to the form, 3 only to the extent that a connection, by and 4 between who? 5 MS. ZETTLER: Somebody at Lilly. 6 A. Well, I assume you are 7 referring to the sentence we discussed earlier 8 about some patients having converted from severe 9 depression to agitation within a few days. 10 Q. Right. 11 A. I'm not sure what you are 12 asking me beyond what we have already talked 13 about. 14 Q. Does this imply to you that 15 the people who converted from severe depression 16 to agitation within a few days, converted because 17 of the use of Fluoxetine? 18 A. That's certainly one 19 possibility. As I discussed earlier, in an open 20 label study of this sort, without any information 21 on the frequency with which this occurs in 22 treated patients -- patients treated with 23 Fluoxetine, versus patients who would be treated 24 with placebo, it's difficult to make a judgment Page 391 1 about cause and effect. 2 Q. Do you know if any studies -- 3 clinical trials were done to study whether or not 4 this phenomenon would occur because of 5 Fluoxetine? 6 A. Yes, the open -- the 7 double-blind studies that are mentioned in the 8 third paragraph of this document, would certainly 9 have been designed to document whether any side 10 effect, this one or any other, was related to the 11 administration of Fluoxetine, just the same as 12 the purpose was to determine whether the 13 efficacy, if any, was related to Fluoxetine. 14 Q. In your opinion, did the 15 double-blind study show that there was a 16 relationship between the use of Fluoxetine and 17 the occurrence of agitation in some patients 18 suffering from depression? 19 MR. MYERS: I object to the form, only 20 to the extent I think that may be a medical 21 question. But if you know, tell her. 22 A. I don't remember how the -- 23 what the -- how the side effects are listed, for 24 example, in the package literature, whether the Page 392 1 term agitation is used or not, to be honest. 2 Q. Okay. I'm not asking what's 3 listed in the package insert, I'm asking what 4 your recollection is that was a result of the 5 controlled -- double-blind controlled studies 6 that you referred to earlier, that proved to you 7 that the drug was efficacious in treating 8 depression in humans? 9 A. Well, the package literature 10 would have been based on those studies and 11 subsequent ones. It would be based on the 12 largest compilation of information, that's why I 13 referred to it. And again, from either that 14 total compilation or any subset thereof, I don't 15 specifically remember whether the term agitation 16 was used to describe side effect or not, I'm 17 sorry. 18 Q. Is it your testimony that the 19 adverse event listed in the package insert have a 20 causal relationship with Fluoxetine? 21 A. Those side effects which occur 22 in the Fluoxetine treated group at a 23 significantly higher rate incidence than in the 24 placebo group, could logically be considered to Page 393 1 be possibly a result of the drug, yes. 2 Q. Is it true that just because 3 you see behavioral change in an animal that that 4 can be related to a behavioral change in a human 5 with the use of a particular drug? 6 A. I'm sorry, could you rephrase 7 that? I don't understand what you mean. 8 Q. In other words, we talked 9 about decreased food intake in some of the 10 animals that were tested, do you recall that? 11 A. Yes. 12 Q. Just because decreased food 13 intake occurs in rats on Fluoxetine, does that 14 necessarily mean that it's going to occur in 15 humans? 16 A. It certainly doesn't 17 necessarily mean that, the -- in general, drugs 18 which suppress food intake in rats, which have 19 been studied in humans, do also suppress food 20 intake in humans, but there may be exceptions. 21 Q. Isn't it generally true that 22 just because you see a particular reaction or 23 physiologically or behaviorly in animals, does 24 not necessarily mean that that reaction is going Page 394 1 to translate into humans? 2 A. I think in general there can 3 be expected such a translation, it does not 4 always occur. 5 Q. For instance, 6 phospholipidosis, you saw that in dogs that were 7 on Fluoxetine, correct? 8 A. That's correct. 9 Q. And you didn't necessarily see 10 that, at least in the same rates as in humans, 11 correct? 12 A. What you're overlooking, I 13 think, is that those studies were seen in dogs in 14 toxicology studies. It's quite probable, I would 15 imagine, that were similar kinds of doses given 16 to humans, that is toxic doses, that 17 phospholipidosis probably -- might well occur. 18 But it doesn't occur, so far as we know, at 19 therapeutic doses. 20 Q. You weren't concerned about -- 21 when that issue came up, you weren't concerned 22 about toxic levels necessarily in humans 23 producing phospholipidosis, were you? 24 MR. MYERS: Let me object to the form. Page 395 1 When you say when the issue came up, you mean -- 2 MS. ZETTLER: Phospholipidosis in 3 drugs. 4 MR. MYERS: Right, but when he talked 5 about it yesterday or when they went to the FDA 6 back in 1991? 7 MS. ZETTLER: When it first came out, 8 when they went to the FDA. 9 A. There would of course have 10 been no intent to give toxic doses to humans. 11 Q. You were concerned or the 12 group was concerned that the occurrence of 13 phospholipidosis in dogs at toxic levels may 14 translate in some way to the occurrence of 15 phospholipidosis in humans, not necessarily at a 16 toxic level of Fluoxetine? 17 MR. MYERS: Before he answers, let me 18 object to the form, because I don't think you 19 quite got his prior testimony straight, unless 20 it's somewhat mischaracterized. But if you can 21 answer that question, do it. 22 A. I do not understand the 23 question, I'm not sure what you are asking. 24 Q. Why would you go to the FDA if Page 396 1 you gave toxic levels of Fluoxetine in dogs and 2 they developed phospholipidosis, why would you 3 bring that information to the FDA? 4 A. Because it is a rather unusual 5 kind of toxicology. And as we are a very 6 cautious company, whenever we find any effects 7 that we have reason to have any level of concern 8 about, we try to investigate them very thoroughly 9 and we wanted to take advantage of the additional 10 experience that the FDA might have with matters 11 of this sort so that we were sure we investigated 12 it in the best way possible to determine if there 13 was any implications with regard to doing human 14 studies with this compound. 15 Q. What, to your knowledge, was 16 done on the part of Eli Lilly to investigate the 17 possible relationship between the Fluoxetine use 18 and the occurrence of violent-aggressive behavior 19 in human beings? 20 A. Are you asking this question 21 in the context of the earlier one, what was done? 22 Q. No, I'm asking you this 23 question in the context of the question. To your 24 knowledge, what did Eli Lilly do to investigated Page 397 1 the claim that Fluoxetine use could produce 2 violent aggressive behavior in human beings? 3 A. So the question is, after the 4 claim was made, what was done to investigate 5 that? 6 Q. Right. 7 A. That was what I was asking for 8 clarification on. One of the major things that 9 was done was a very careful reanalysis of the 10 entire data base from the controlled clinical 11 studies to investigate whether, in fact, there 12 was any evidence to support such claims and while 13 I am not -- I was not involved in that and I'm 14 not intimately familiar with it, I am aware that 15 the results of that, I believe, were published 16 with John Heiligenstein as first author and that 17 they suggest, I believe, as many people might 18 have predicted from the rather extensive 19 literature that surrounds the possible role of 20 serotonin in aggressive behavior, based more on 21 animal studies than human studies, that indeed 22 there was a reduced incidence, rather than an 23 increased incidence, in the Fluoxetine treated 24 patients. Page 398 1 Q. What else was done besides 2 this careful reanalysis of the data base? 3 A. At the moment, I don't recall 4 other things that were done, but I would not have 5 been involved in those other things personally. 6 Q. To your knowledge, were any 7 double-blind controlled studies set up to 8 specifically study this phenomena? 9 A. Any further studies beyond 10 those which have been done? 11 Q. Yes. 12 A. Not that I recall. 13 Q. To your knowledge, were the 14 studies that were reanalyzed, were any of those 15 studies set up to specifically study that 16 phenomena? 17 A. They were not, so far as I 18 know. 19 Q. Are you aware of any studies 20 that Lilly did on schizo-affective disorders and 21 the use of Fluoxetine, treating it? 22 A. If such studies were done, I'm 23 sure I heard about them, and I don't have 24 specific recollection of that. Page 399 1 Q. What makes you say that this 2 was -- that the reanalysis was a careful 3 reanalysis of the data base? 4 A. Because I am sure those people 5 who were doing it were very concerned with a 6 careful study of the data to find out if there 7 was any basis for the statements that some people 8 were making. 9 Q. Any other reason besides that 10 reason? 11 A. I think that's the main 12 reason. 13 Q. Do you know exactly which 14 studies they reanalyzed or which data they 15 reanalyzed? 16 A. I believe it was virtually all 17 of the controlled double-blind studies that were 18 available at that time. 19 Q. Both the United States and 20 outside the United States? 21 A. I have no involvement and I 22 could not answer that specific question and I 23 think it would have -- well, period. 24 Q. If not all of the controlled Page 400 1 studies were reanalyzed, would that have an 2 impact on the validity of the reanalysis in your 3 mind? 4 MR. MYERS: Let me object to the form, 5 only to the extent that since he is only aware of 6 it, he didn't do it, I don't know that he is able 7 to make that assessment. 8 MS. ZETTLER: Well, he's making a very 9 careful analysis, Larry, I'm trying to find out 10 why he is careful. 11 MR. MYERS: That's a different 12 question. I object to the form of the question. 13 If you know the answer, tell her, Doctor Fuller. 14 A. I don't know the answer to 15 that question. 16 Q. You don't have an opinion 17 either way as to whether or not it would have an 18 impact on the validity of the analysis whether or 19 not all of the studies were actually reanalyzed? 20 A. So far as I know, all the 21 studies that had useful information were analyzed 22 and if there were studies that were not included, 23 there would have been some reason, which I don't 24 know. Page 401 1 Q. Who decided whether or not a 2 particular study had useful information? 3 A. I would have no way of knowing 4 that. 5 Q. Did you have any input, 6 whatsoever, in the manuscript that Doctor 7 Heiligenstein wrote? 8 A. No, I did not, to the best of 9 my recollection. 10 Q. How about suicidality related 11 to the use of Fluoxetine, what did Lilly do to 12 investigate that issue once it arose? 13 A. I believe the same thing. A 14 reanalysis of all the available data and, I 15 believe, a careful monitoring of all future 16 reports of any sort. 17 Q. When you say future reports of 18 any sort, what do you mean? 19 A. Any information that would 20 have come in from any source pertaining to that 21 topic. 22 Q. In your opinion, are the 23 clinical investigators used by Lilly to conduct 24 the double-blind controlled studies competent Page 402 1 individuals, generally? 2 A. The intent is certainly to 3 select competent individuals. I would have not 4 much basis for making those judgements myself 5 because I have little participation in the 6 selection of clinical investigators. 7 Q. Have you ever seen any 8 clinical report forms from any particular 9 double-blind controlled studies? 10 A. I believe I have seen them. 11 Q. Have you reviewed them? 12 A. No. 13 Q. Have you done a study of the 14 results that were -- an independent study on your 15 own of any of the results of a particular 16 clinical trial? 17 A. No. 18 Q. Earlier you stated that if the 19 benzodiazepines were in fact given to treat 20 agitation suffered by people who were on 21 Fluoxetine, that as long as -- and if I'm getting 22 this wrong, let me know -- but as long as the 23 adverse event itself was recorded, it wouldn't 24 necessarily mask a side effect profile of Page 403 1 Fluoxetine to administer the benzodiazepines, is 2 that correct. 3 MR. MYERS: I object to the form, only 4 because I don't think you did get it right, I 5 think you said something different. 6 MS. ZETTLER: He can tell me. 7 MR. MYERS: I understand, I'm just 8 objecting to the form of the question. 9 A. Yes, I think what I said was 10 that not only the event would be recorded, but 11 also the use of benzodiazepines would be 12 recorded. 13 Q. If the use of benzodiazepines 14 was recorded but the event was not recorded, 15 would that impact the validity of that particular 16 clinical trial results, in your opinion? 17 MR. MYERS: Let me object to the form 18 of the question to the extent that Doctor Fuller 19 has testified yesterday and today that he did not 20 do or supervise clinical trials and I don't know 21 that he is able to make that conclusion. But if 22 you can answer it, go ahead. 23 A. Well, you may be asking about 24 details that I would have no way of knowing, but Page 404 1 the recording of benzodiazepine use, I assume 2 would itself signify an event, so I'm not sure 3 how you could have one without the other. 4 Q. You have reviewed clinical 5 report forms generally, correct, on a couple of 6 different studies? 7 MR. MYERS: Let me object to the form. 8 He said he had seen report forms and in an answer 9 to a subsequent question said he hadn't reviewed 10 any. 11 Q. Not have filled out one, but 12 the form itself, are you familiar with how the 13 form is structured, generally? 14 A. My earlier testimony was that 15 I feel sure I have seen such reports, but I would 16 not consider any scrutiny that I had done of them 17 to justify the use of the word review. 18 Q. Did you, yourself, write any 19 papers on Fluoxetine and violent-aggressive 20 behavior? 21 A. Specifically, on the subject 22 of Fluoxetine and violent-aggressive behavior, 23 no. 24 Q. How about Fluoxetine and Page 405 1 aggressive behavior? 2 A. I have written a lot of papers 3 on Fluoxetine, or on the subject of serotonin 4 pharmacology, and in the context of some of those 5 papers, I have talked about various aspects of 6 serotonin -- physiological roles of serotonin in 7 brain and certainly in some of those papers there 8 would be mention of aggressive behavior, so that 9 the words Fluoxetine and aggression, for example, 10 might, I would imagine, have both appeared in 11 some of the papers I have written. 12 Q. Prior to the issue being 13 raised in the media, was Lilly studying whether 14 or not there was a relationship between the use 15 of Fluoxetine and violent-aggressive behavior? 16 A. I don't believe so. 17 Q. How about the use of 18 Fluoxetine and suicidal ideation or suicidal 19 behavior? 20 A. Well, I think that would be 21 inheritant in the study of depression since 22 suicidal ideation and suicidal behavior are 23 components of -- common symptoms of depression. 24 Q. I mean as a specific issue, Page 406 1 not as a portion of the depression study. 2 A. So far as I know, not as any 3 study that wasn't a depression study. 4 Q. Were you involved in the 5 registration of Fluoxetine in any country other 6 than the United States? 7 A. What do you mean by involved? 8 Q. Did you have any input on 9 information that was given to any other 10 governmental agency outside the USA or did you 11 perform studies in support of any application in 12 any other country by Lilly for marketing of 13 Fluoxetine? 14 A. Well, certainly the same 15 preclinical data that I generated, that were 16 included, reported to the U.S. Food and Drug 17 Administration, were also reported to other 18 regulatory agencies, and in some cases I probably 19 wrote summaries of the pharmacologic data for 20 other agencies. As far as dealing directly with 21 any agencies in other countries, I did not. 22 Q. Do you recall a question of 23 the safety profile of Fluoxetine or any 24 particular problem with the safety profile of Page 407 1 Fluoxetine being raised by governments outside 2 the United States? 3 A. I'm sorry, say it again. 4 Q. Sure. Let me ask it this way: 5 Do you recall that in 1984 or 1985, the German 6 government raised the issue as to whether or not 7 Fluoxetine was a stimulant as opposed to a 8 sedative antidepressant? 9 MR. MYERS: Let me object to the form, 10 because I don't think you precisely phrased the 11 question that the Germans asked. But if you know 12 the answer to the question, tell her. 13 A. In a general sort of way, I 14 think I remember the issue with regard to the 15 German government. I certainly don't recall 16 specifically that it was in 1984 or 1985, nor do 17 I recall the specific questions or concerns that 18 were posed by the German regulatory agency. 19 Q. Do you recall that Lilly 20 withdrew its application or its petition for 21 marketing of Fluoxetine in Germany in the 22 mid-1980's because they had received an intent to 23 reject indication from the German government? 24 A. If that happened, I probably Page 408 1 was aware of it at the time, but do I remember it 2 now, no, I don't. 3 Q. Are you aware that in the 4 package insert currently used in Germany for 5 Fluctin or Fluoxetine suggests that a sedative be 6 administered concomitantly with Fluoxetine in 7 people who pose a suicidal risk or suffer from 8 anxiety? 9 MR. HARRIS: I'm going to object 10 again. This witness has not been qualified as a 11 medical doctor, he is a Ph.D, and to that extent 12 we do not believe it is a proper predicate laid 13 and calls for speculation on the part of this 14 witness and he is not competent to testify on the 15 administration of a sedative for suicide or 16 suicidal ideation. 17 MS. ZETTLER: I'm asking him whether 18 or not he is aware what the package insert says, 19 he's already referred to the U.S. package insert 20 numerous times. 21 MR. HARRIS: Same objection. 22 MR. MYERS: I object, only because to 23 the extent you've undertaken to recite what is in 24 the German insert, I don't know that you have Page 409 1 stated it precisely. 2 MS. ZETTLER: Okay. Here, I'll read 3 it precisely. 4 Q. Doctor, are you aware that the 5 current package insert for Fluoxetine states 6 under the section titled, Risks Patients, Risk of 7 Sucicide, colon, Fluctin does not have a general 8 sedative effect on the central nervous system, 9 therefore for his or her own safety the patient 10 must be sufficiently observed until the 11 antidepressant effect of Fluctin sets in. Taking 12 an additional sedative may be necessary, this 13 also applies in cases of extreme sleep 14 disturbances or excitability. Were you aware 15 that this says that? 16 MR. MYERS: Is there a date on that 17 that you are reading from? 18 MS. ZETTLER: 1993. 19 A. To the best of my 20 recollection, I have not read any part of the 21 German package insert, and so I did not have any 22 specific knowledge of that passage. 23 Q. To the best of your 24 recollection, has the U.S. package insert ever Page 410 1 contained a similar statement? 2 A. Not that I recall. 3 Q. Do you have an explanation why 4 the German package insert has that statement and 5 the U.S. does not? 6 A. None whatsoever. 7 Q. Were you aware in June of 1984 8 that the German government felt that there was a 9 disagreement between patients' and doctors' 10 judgment of efficacy during the clinical trials? 11 MR. MYERS: Let me object to the form 12 of the question, it's awfully vague and 13 ambiguous. This agreement in what? I mean the 14 question is so open-ended and vague, I don't know 15 that it's capable of an intelligent answer. 16 Q. Do you understand what I am 17 talking about? 18 A. As I understood the question, 19 it had to do with whether I was aware of that in 20 1984. 21 Q. No. Are you aware that in 22 1984 the German government raised that issue with 23 Lilly? 24 A. No, I'm not aware of that. Page 411 1 Q. Were you aware that in 1984 a 2 critical issue for the BGA was safety in 3 long-term treatment with Fluoxetine? 4 A. I may have learned that at one 5 point or another, but I don't remember it now. 6 Q. Are you aware that patients 7 that posed a serious suicidal risk were excluded 8 from the outpatient clinical trials? 9 A. In Germany you are referring 10 to? 11 Q. No, in the United States. 12 A. I probably was aware of that. 13 Q. Do you know why they were 14 excluded? 15 MR. MYERS: Before he answers, let me 16 object to the form. That may well be a clinical 17 and thus a medical question, so I object to the 18 form, I don't know that he is qualified to answer 19 that. But if you know, Doctor, if you have some 20 information, tell her. 21 A. Well, I would remind you that 22 I was not involved in the planning or monitoring 23 of the clinical trials, so I do not have any 24 intimate knowledge of the protocols or the Page 412 1 reasons for their design, but I would imagine 2 that, if that condition as you described 3 occurred, it was because it was the best judgment 4 of the clinical investigators that the interest 5 of the patient would be best served by not 6 including them in the study. 7 Q. Do you recall how many 8 inpatient studies of suicidal patients were 9 conducted by Lilly using Fluoxetine prior to 10 January 1st, 1990? 11 A. No, I would have no reason to 12 know that. 13 MR. MYERS: Did you say inpatient of 14 suicidal -- inpatient studies of suicidal 15 patients? 16 MS. ZETTLER: Right. 17 Q. How about inpatient studies of 18 severely depressed patients? 19 A. Again, I would have no reason 20 to know that. 21 Q. Have you ever heard of a 22 Doctor Ivan Miller? 23 A. Not to my recollection. 24 Q. Were you aware that in 1984 Page 413 1 the BGA felt that Fluoxetine had an accumulation 2 effect physiologically -- biologically? 3 MR. MYERS: I object to the form and 4 terminology "accumulation effect" as being 5 without definition, vague. But if you know, 6 Doctor, tell her. 7 A. I don't think I have an 8 awareness of any of the BGA attitudes in 1984. 9 Q. Were you aware -- were you 10 ever made aware that the German government, at 11 any time, felt that Fluoxetine had a stimulant -- 12 or a stimulating activity drug? 13 MR. MYERS: Object to the form, I 14 don't think that's an accurate characterization, 15 but if you know, tell her. 16 A. I believe I testified earlier 17 that I was aware that there was some concern by 18 the German regulatory agency on that general 19 subject, but I don't remember specifically about 20 the terms that you used. 21 Q. Have you been aware, at any 22 time, that the German government, at any time, 23 was concerned about the possible association of 24 suicidal ideation and the use of Fluoxetine? Page 414 1 MR. MYERS: I object to the form for 2 the same reason. If you know, tell her. 3 A. I don't know -- I don't have 4 any specific recollection of those specific 5 concerns. If you're reading from a document that 6 I was an addressee on, I probably read it, but I 7 don't remember events in 1984 that concerned 8 issues that I was only tangentially involved in. 9 Q. I mean, at any time, not just 10 '84, as far as the stimulant profile and 11 suicidality questions were concerned? 12 A. I testified earlier, that on 13 terms of what you refer to as a stimulant, I have 14 a recollection that this general issue has come 15 up with regard to Fluoxetine and that I, for 16 example, have supplied pharmocologic evidence to 17 illustrate that Fluoxetine is in no way like 18 amphetamine or other stimulant drugs of that 19 class. I don't specifically remember that those 20 incidents had to do with the German regulatory 21 agency, but they might have. 22 Q. Have you done studies 23 specifically comparing the effects of Fluoxetine 24 and the effects of amphetamines on lab animals? Page 415 1 A. I have done research on 2 amphetamine for probably at least twenty-five of 3 the thirty-one years I have been at Eli Lilly and 4 Company, and I have done research on Fluoxetine 5 for, what would it be, twenty-two years. So I 6 have done a fair number of pharmacological 7 experiments on these two drugs, yes. 8 Q. Why is it your opinion that 9 the two drugs are not similar? If you could just 10 give me a general -- are not similar. 11 A. Fluoxetine is a selective 12 inhibitor of serotonin uptake and it does not 13 have any other relevant pharmacologic actions, as 14 far as we are aware. Amphetamine does not have 15 that pharmacologic action, instead its principle 16 pharmacologic effects are as releaser of 17 catacoamines, particularly dopamine and also 18 norepinephrine. It has a set of pharmacologic 19 actions that result from the release of 20 catacoamines, which are, for the most part, 21 totally different from the pharmacologic actions 22 of serotonin uptake inhibitors such as 23 Fluoxetine. 24 Q. How about the behavioral Page 416 1 effects of the drugs, are there similarities? 2 A. There's virtually no 3 similarity. 4 Q. Do lab animals on amphetamines 5 demonstrate a lowered food intake? 6 A. I wouldn't personally include 7 that in a list of behavioral effects. The one 8 thing that drugs which release dopamine do that 9 is in common with the drugs which block serotonin 10 uptake or release serotonin, is reduce appetite, 11 and that's because food intake is regulated not 12 only by serotonergic neurons, but also by 13 catacoamine neurons to the brain. So it's 14 possible to reduce food intake by affecting 15 either of those neuro pathways, and the 16 characteristics of drugs which act through those 17 two distinct pathways are quite different. The 18 reduction of food intake that is elicited by 19 amphetamine is readily distinguishable from the 20 reduction in food intake that is elicited by 21 Fluoxetine, in that, for example, Fluoxetine 22 selectively reduces carbohydrate intake, as other 23 drugs acting through the serotonin mechanism do, 24 and which amphetamine does not do. Fluoxetine Page 417 1 supresses the insulin induced hyperphagia, 2 overeating in rats, which amphetamine and other 3 catacoamine acting drugs do not do, and 4 Fluoxetine reduces stress-induced eating in rats, 5 which amphetamines and other drugs acting through 6 a cataco mechanism do not do. So the effects of 7 Fluoxetine and amphetamine on food intake are 8 readily distinguishable from one another. 9 Q. The fact of the matter is, 10 you're looking at the two rats, both of them are 11 eating less, correct, for whatever reason? 12 A. If that's all you're looking 13 at, you would see a decrease in both cases. 14 Q. How about agitation, have you 15 seen agitation in both rats on Fluoxetine and 16 rats on amphetamines? 17 A. As I have testified earlier, 18 we do not see any observable behavioral changes 19 in rats treated with Fluoxetine. In rats treated 20 with amphetamine, observable behavioral changes 21 are very apparent. There is pronounced 22 hyperactivity and this can be observed or it can 23 be quantitated in various kinds of cage devices 24 that measure -- that allow one to measure Page 418 1 hyperactivity and the studies that have been done 2 show clearly that Fluoxetine does not cause that 3 amphetamine type of hyperactivity. 4 Q. How about sleep disturbance, 5 do you see sleep disturbance in both animals? 6 A. No. So far as I know, 7 Fluoxetine causes no changes in sleep that I 8 would characterize as a sleep disturbance. 9 Q. Decreased REM sleep is not a 10 sleep disturbance? 11 MR. MYERS: Wait a minute. Were you 12 done with your answer before you go on to 13 another? 14 A. I was not done with my answer, 15 but I can incorporate an answer to the second 16 question in my continuation. With amphetamine, 17 while I do not remember studies specifically on 18 sleep, knowing what amphetamine treated rats look 19 like, I would feel sure that if you studied them 20 during a period in which they were normally 21 sleeping, they would not be sleeping, with 22 amphetamine. And these studies that you are 23 referring to, I imagine, on REM sleep that were 24 done by Doctor Slater and colleagues and also Page 419 1 done by Doctor Pastal and colleagues at the 2 University of Pittsburg, I believe all showed 3 that there was no decrease in total sleep time in 4 rats that were treated with Fluoxetine -- or in 5 cats, I believe. And the reduction -- the 6 significant reduction in REM sleep that was 7 observed, is a change only in one quantitatively 8 rather minor component of sleep and I don't think 9 most people would refer to that as a sleep 10 disturbance. 11 Q. You think REM sleep is a minor 12 portion of sleep? 13 A. Quantitatively, it is, yes. 14 Q. Are you talking about in 15 animals as well as humans, or just in animals? 16 A. The data I am referring to are 17 in animals, rats and cats, yes. 18 Q. Do you feel that REM sleep is 19 quantitatively a minor portion of the sleep cycle 20 in humans? 21 A. I think it probably is. 22 Q. Are you aware that REM sleep 23 deprivation in human beings has produced 24 psychosis in some studies? Page 420 1 A. No, I'm not specifically aware 2 of that, although I may have seen publications on 3 that subject. 4 (PLAINTIFFS' EXHIBIT 13 WAS 5 MARKED FOR IDENTIFICATION AND 6 RECEIVED IN EVIDENCE.) 7 Q. Okay. Have you had a chance 8 to review Exhibit 13? 9 A. I have seen it and glanced 10 through it. 11 Q. Do you recognize it? 12 A. It appears to be a collection 13 of E-mail messages that relate to the subject 14 that we discussed earlier. 15 Q. And that subject meaning 16 whether or not Fluoxetine acts as a stimulant or 17 has amphetamine-type properties? 18 A. That's correct. 19 Q. Who is Hans Weber? 20 A. Hans Weber, I believe, was and 21 maybe still is the Lilly medical representative 22 in Germany. 23 Q. Who asked you for this 24 information on the chemical structures -- Page 421 1 comparative chemical structures of Fluoxetine and 2 amphetamines? 3 A. I would have to review this to 4 see if the answer is apparent here because I 5 don't remember it. Well, this seems to indicate 6 that on February 6th, 1991, Doctor Leigh Thompson 7 sent a message to me. 8 Q. Are you referring to the 9 fourth page of the Exhibit? 10 A. Yes, I am. 11 Q. Okay. Doctor Thompson is 12 asking you about the abuse potential, is he not? 13 A. Yes. 14 Q. And I mean abuse potential of 15 Fluoxetine, correct? 16 A. That is correct, I believe. 17 Q. And that is apparently in 18 response to an inquiry by the BGA? 19 A. It is apparently in response 20 to the message which is immediately below his 21 message saying from Hans Weber. 22 Q. Okay. And in that message he 23 states that Fluoxetine was discussed extensively 24 at a meeting apparently between the BGA and AMK? Page 422 1 A. Yes. 2 Q. And towards the bottom of the 3 page there are three bullet type 4 differentiations, do you see those? 5 A. Yes. 6 Q. The last one says, also the 7 question was raised whether Fluoxetine could be 8 an amphetamine like drug which may explain 9 stimulating and anorectic effects. Do you see 10 that? 11 A. Yes, I do. 12 Q. And it goes on to say that it 13 turned out that not enough was known about the 14 pharmacology in this respect, correct? 15 A. Yes, I see that. 16 Q. Did you provide, other than 17 the explanations that are also attached to this 18 part of this exhibit, to Doctor Thompson or 19 anybody else pharmacological data in support of 20 your explanation, or what was there attached to 21 this exhibit? 22 MR. MYERS: When you say 23 pharmacological data, do you mean references or a 24 bunch of numbers. Page 423 1 MS. ZETTLER: References, his results 2 of any of his studies, his findings, anybody 3 else's findings. 4 A. You said in support of my 5 explanation, what explanation are you referring 6 to? 7 Q. The one on the first page of 8 the Exhibit that says, I find it surprising that 9 anyone would consider the chemical structures of 10 Fluoxetine and amphetamine to be similar, and 11 your explanation that follows after that. 12 A. I recall that I have, on 13 occasion, actually drawn out the chemical 14 structures of many of these drugs mentioned on 15 this page, because to me it was so absurd that 16 anyone would suggest a chemical similarity 17 between Fluoxetine and amphetamine, and I have 18 suggested to people that they might show that 19 page of structures and ask people to pick out 20 which compounds they viewed to be structurally 21 similar, and if anyone who didn't know what those 22 drugs were would ever have pointed to Fluoxetine 23 molecule as being similar to the amphetamine 24 molecule, I would have been greatly surprised. Page 424 1 Q. Let's try my question again. 2 Did you provide Doctor Thompson or anybody else 3 information such as result studies, medical 4 literature, scientific literature, drawings of 5 the different chemical structures, in response or 6 in support of your response that is here, set out 7 here in Exhibit 13? 8 MR. MYERS: When he did this? 9 MS. ZETTLER: Right. 10 A. I think what I just described 11 to you was indeed information that would pertain 12 to this and I think what I said was I remember 13 preparing that. What I do not remember is 14 whether I supplied that at this time to either 15 Doctor Thompson or to anyone else. 16 Q. Okay. Besides the drawings 17 and the explanation of the drawings, did you give 18 them any scientific literature, any papers? 19 A. Well, I referred in this 20 message to the fact that in November, 1985, 21 Martin Hynes, David Wong and myself, prepared a 22 report on Fluoxetine in its preclinical 23 pharmacology, in which there were references 24 given and reprints supplied that document several Page 425 1 of the points that I made in this message. 2 Q. Anything else besides that 3 report? 4 MR. MYERS: That exist in the 5 literature or that he sent? 6 MS. ZETTLER: No, that he sent. 7 A. I remind you that I have told 8 you I don't remember whether I sent anything in 9 relation to this particular E-mail message, but 10 that on different occasions I have provided such 11 information to anyone who asked for it. 12 Q. How about in response -- 13 directly in response to questions raised by the 14 BGA? 15 A. This is a response to a 16 question raised by the BGA, this particular 17 response is just that. 18 Q. Right. 19 A. If you are asking were there 20 others, I do not know, there may have been. 21 Q. Who is Professor 22 Mueller-Oerlinghausen? Look at the third from 23 the last page. 24 A. He is a psychiatrist in Page 426 1 Germany. 2 Q. Does he work for the BGA? 3 A. I don't know, he doesn't work 4 full-time for the BGA, I don't believe. 5 Q. The last paragraph on PZ2576 6 1702, which is the page we were just looking at, 7 states, Professor Mueller-Oerlinghausen can take 8 this point back to the next meeting if armed with 9 specific information. Do you recall whether or 10 not he was working with or consulting with the 11 BGA at that time? 12 A. I don't even know if I was 13 aware of it at the time and if I was, I don't 14 recall it now. He apparently had some 15 involvement. 16 Q. And the next page it says, 17 detailed information would be most appreciated. 18 Also M-O, which I take to mean 19 Mueller-Oerlinghausen, knows Ray Fuller and a 20 direct telephone contact might help. Do you see 21 that? 22 A. Yes, I do. 23 Q. Did you call Doctor 24 Mueller-Oerlinghausen? Page 427 1 A. Not to the best of my 2 recollection, no. 3 Q. Were you asked to besides this 4 E-Mail? 5 A. I doubt it. 6 Q. Why do you doubt it, why do 7 you doubt that you were asked? 8 A. I don't remember being asked, 9 let me say it that way. 10 Q. Also in the last, I guess it's 11 the last page of the Exhibit, first middle of the 12 page it says, Ray, David, Lou, Rich - what 13 package of information can we gather for 14 Professor Mueller-Oerlinghausen. 15 A. Yes. 16 Q. It says, he is very objective 17 and played a key role with the BGA through the 18 AMK, what is the AMK? 19 A. I don't know. 20 Q. Who is Bob Thompson? 21 A. Bob Thompson is a physician in 22 our medical division. 23 Q. Is he still there? 24 A. Yes, he is. Page 428 1 Q. Does this refresh your 2 recollection as to whether or not you helped put 3 together a package of information for Professor 4 Mueller-Oerlinghausen? 5 A. I testified earlier that I 6 have supplied, in addition to this E-mail 7 message, which mentions specific information that 8 I had put together that I have supplied 9 information to anyone who asked for it, I don't 10 believe I have ever sent anything directly to 11 Doctor Mueller-Oerlinghausen, but it's quite 12 possible that things that I have prepared were 13 sent by other people to him. I don't remember 14 that I am aware of that specifically. 15 Q. I'm a little confused about 16 the down regulation of receptors. Not so much 17 about how it works or after your explanation 18 yesterday, but what types of receptors are 19 serotonin subtype receptors are down regulated or 20 you found down regulation in? 21 MR. MYERS: You haven't heard enough 22 about that? 23 MS. ZETTLER: I want to know what 24 subtypes are down regulated. I can't get enough Page 429 1 of it. 2 A. The study of serotonin 3 receptor down regulation in response to 4 Fluoxetine or other antidepressant drugs, has 5 principally focused on two general types of 6 receptors, what is called 5HT-2 receptor and the 7 5HT-1 receptor. In 1979, those two receptors 8 were defined and have been studied since then. 9 What has happened in recent 10 years, is the recognition that the 5HT-1 site is 11 not a single receptor, but in fact is a complex 12 of at least seven different receptors called 13 5HT-1A, 1B, 1C, 1D, 1E and 1F. And the studies 14 that have been done generally -- the studies of 15 down regulation that have been done, with 16 repeated treatment with drugs such as Fluoxetine, 17 have generally used radioactive serotonin as the 18 radioligand to label the 5HT-1 receptors. That's 19 the type of studies that, for example, David Wong 20 did with Fluoxetine. His studies and the studies 21 of others have shown that Fluoxetine causes a 22 decrease in the number of tritiated serotonin 23 binding sites, tritiated Fluoxetine binding 24 sites. Today, we understand that this Page 430 1 radioactive serotonin is actually labeling this 2 complex of 5HT-1 receptors, not a single 3 receptor. So which of those specific 5HT-1 4 receptors has undergone down regulation, which 5 one or which ones, is a question that remains to 6 be answered, and it can be answered only when 7 there are specific radioligands available for 8 study, each of those receptors subtypes 9 selectively. So all one can say now, I think, is 10 that Fluoxetine causes a decrease in the number 11 of radioactive serotonin binding sites. It does 12 not cause a decrease, I think according to most 13 studies if not all studies, in the number of 14 5HT-2 receptors. There are a number of 15 additional serotonin receptors that have now been 16 discovered such as 5HT-3, 5HT-4, 5HT-5, 5HT-6 and 17 5HT-7 receptors. To the best of my recollection, 18 none of those receptors have been studied, as 19 yet, to see if they undergo down regulation in 20 response to antidepressant drugs, including 21 Fluoxetine. The one more piece of information is 22 that there are other kinds of studies which 23 suggest that the 5HT-1 autoreceptor may undergo 24 down regulation with Fluoxetine and other Page 431 1 antidepressant drugs and that probably is the 2 5HT-1A autoreceptor. That's about the current 3 state of knowledge about serotonin receptors' 4 down regulation insofar as Fluoxetine is 5 concerned. 6 Q. Do all of these serotonin 7 subtype receptors have autoreceptors also? 8 A. The autoreceptors that are on 9 serotonin neurons are currently believed to be 10 principally of three types. The 5HT-1A receptor 11 is mainly on serotonin cell bodies and on 12 serotonin nerve terminals there are probably 13 5HT-1B and 5HT-1D receptors. 14 Q. B and D? 15 A. B and D. 16 Q. And let me make sure I 17 understand you correctly, all the autoreceptors 18 are thought to be affected? 19 A. It's not so clear whether all 20 of those are affected or not, partly because the 21 method of study of those autoreceptors was not 22 radioligand binding and would not distinguish 23 readily between those subtypes. 24 Q. Again, just a couple of Page 432 1 questions to make sure I understand this. It 2 appears that 5HT-1, subtype 1 -- 3 A. Yes. 4 Q. -- is affected by down 5 regulation, or at least some of the group of 6 5HT-1? 7 A. After a Fluoxetine treatment, 8 yes. 9 Q. And two does not seem -- you 10 said a decrease in receptors, does that indicate 11 that there may be a down regulation but not a 12 decrease in receptors? 13 A. No. The meaning was that that 14 people who have studied 5HT-2 receptors with 15 Fluoxetine have generally found no change. 16 Q. How about turnover? 17 A. Turnover of serotonin. 18 Q. Right. Is that affected 19 around all of the neurons or is there a 20 relationship between the down regulation and the 21 decreased turnover? 22 A. I don't think there's any, 23 necessarily, necessary relationship between those 24 two events, because the decrease in turnover is Page 433 1 something that occurs rapidly or within minutes 2 after a single dose of Fluoxetine, whereas the 3 change in receptors is something that occurs 4 after repeated daily treatment with Fluoxetine. 5 The decrease in turnover occurs in many, if not 6 all, places in the brain where serotonin neurons 7 are found. 8 Q. So that affects the serotonin 9 neuron itself, not differentiating by 10 autoreceptors or receptor subtypes or anything 11 like that? 12 A. They are effects that almost 13 certainly are mediated by increased activation of 14 autoreceptors. Probably both 5HT-1A cell body 15 autoreceptors and the nerve terminal 16 autoreceptor. 17 Q. Would there be a decreased 18 turnover in 5HT-2 receptors, the serotonin nerves 19 that are related to those neurons with those 20 receptors? 21 A. I think you're confusing two 22 different -- there are not specific receptor 23 subtypes that are associated with any particular 24 serotonin neurons. That is, the serotonin neuron Page 434 1 that projects from the raphe nucleus to the 2 cortex, for example, and a serotonin neuron that 3 projects from the raphe nucleus to the 4 hippocampus, may both contain the same kinds of 5 receptors. 6 Q. I think I can short circuit 7 this. 8 MR. MYERS: Let him finish. 9 A. But they are separate 10 serotonin pathways and both of those pathways 11 would undergo a decrease in serotonin turnover in 12 response to an acute treatment with a drug like 13 Fluoxetine. But that is -- that does not have 14 anything directly to do with adapting changes in 15 receptors, but might be for later. 16 Q. So the turnover occurs whether 17 or not the receptor on the postsynaptic neuron is 18 being down regulated? 19 A. Again, the change in turnover 20 occurs rapidly, within minutes, long before there 21 would be any change in the postsynaptic -- any 22 change in the number of postsynaptic receptors, 23 any down -- in anything that we call down 24 regulation. The effect on serotonin Page 435 1 turnover would occur quickly before there was any 2 down regulation, so there wouldn't be any 3 temporal correlation. 4 Q. Okay. Does the decrease in 5 turnover persist until the Fluoxetine or whatever 6 it is that is keeping the serotonin from being 7 taken back up into the neuron is removed, or is 8 that something that readjusts itself over time? 9 A. There's -- it probably does, 10 but there are some -- there are certain findings 11 that relate to that question which I would like 12 to describe. 13 There are findings from Claude 14 De Montigny in Montreal, who has primarily 15 studied electric physiological effects rather 16 than neurochemical effects. So what he is 17 studying is the firing of serotonin neurons and 18 not the turnover of serotonin measured 19 neurochemically. But Claude and his colleague's 20 have evidence that the autoreceptors which 21 initially suppress the function of serotonin 22 neurons as a consequence of there being an 23 increased amount of extracellular serotonin, 24 gradually adapt and what one might call Page 436 1 desensitize over several days, so that initially 2 when you give an uptake inhibitor like 3 Fluoxetine, this decrease in serotonin turnover 4 limits the extent of increased serotonergic neuro 5 transmission as I explained yesterday, and what 6 his findings suggest is that with time, this 7 ceiling may be lifted, that is the neurons now 8 may begin to resume their firing and release more 9 serotonin, while uptake is still inhibited, of 10 course, so that the extent of the increase in 11 extracellular serotonin, i.e. in serotonergic 12 neuro transmission, would actually become greater 13 with time. 14 Q. Okay. Earlier when you 15 testified that you became convinced of 16 Fluoxetine's efficacy in treating depression in 17 humans was after you read -- saw the results of 18 the double-blind studies, do you recall that? 19 A. Yes. 20 Q. At what point did you see 21 those, did you see the results or did you see the 22 works in progress? 23 A. I would have had little 24 exposure to the work in progress. What I would Page 437 1 have seen would have been the analysis of the 2 results at the end of the study. 3 Q. The final reports? 4 A. Yes. 5 Q. Have you ever heard of Dorothy 6 Dobbs? 7 A. Have I ever heard of her? 8 Q. Uh-huh. 9 A. Yes. 10 Q. Who is Dorothy Dobbs? 11 A. She was a -- in the regulatory 12 division at Lilly for a few years. 13 Q. Did you work with Dorothy on 14 many projects related to Fluoxetine? 15 A. She would have been the 16 regulatory -- the key regulatory person for some 17 period of time, I don't remember what that was, 18 but it was, I think, a relatively brief period of 19 time in the earlier stages of Fluoxetine 20 development, as I remember it. 21 Q. Do you recall -- she was a 22 medical doctor, correct? 23 A. I believe that's right. 24 Q. Do you recall Doctor Dobbs Page 438 1 having any complaints as to the way information 2 was being reported to the FDA related to 3 Fluoxetine studies that were ongoing at the time 4 she was working at Lilly? 5 A. No, I don't remember that. 6 Q. When did she leave Lilly? 7 A. I don't remember. 8 Q. Do you know why she left 9 Lilly? 10 A. No, I don't. 11 Q. Were you aware that Doctor 12 Dobbs was promised a job higher up than she ended 13 up being at Lilly and then was denied that job? 14 MR. MYERS: I object to the form. If 15 you are relying on what some other witness told 16 you way back, I don't think you characterized it 17 correctly. 18 MS. ZETTLER: I'm asking if he's 19 aware. 20 MR. MYERS: But you're stating it as a 21 fact, though. 22 A. I would have no knowledge of 23 things like that in her case, I didn't know her 24 that well. Page 439 1 Q. Is serotonin metabolized any 2 way other than being retaken back up into the 3 neuron? 4 A. That step is not actually 5 referred to as metabolism. The metabolism of 6 Fluoxetine is the -- is its degradation by the 7 enzyme monoamine oxydase, and that is by far the 8 principle route of serotonin metabolism. 9 Q. Where does the degradation by 10 the MAO take place? 11 A. It takes place, the enzyme 12 monoamine oxydase is located on the outer 13 membrane of mitochondria, 14 M-I-T-O-C-H-O-N-D-R-I-A, and virtually every cell 15 in the body has mitochondria containing monoamine 16 oxydase and therefore is capable of metabolizing 17 serotonin. The serotonin in the brain is 18 metabolized within the brain since it doesn't 19 cross the blood brain barrier. 20 Q. Okay. If the serotonin 21 molecule is not taken back up into the serotonin 22 neuron, does it remain active? 23 A. By active, I assume you mean 24 active on a receptor to transmit nerve impulses. Page 440 1 Q. Or capable of being active on 2 a receptor to transport impulses. 3 A. Yes, as long as it remains as 4 an intact serotonin molecule, it would be capable 5 of interacting with a receptor if it comes in 6 contact with one. 7 Q. I can't remember if it was you 8 or Doctor Wong who testified to this, but can the -- 9 what is meant by the serotonin at the site, 10 transport site, not being able to get in because 11 of the Fluoxetine diffusing, do you recall saying 12 something like that? 13 A. Yes. Fluoxetine -- any 14 molecule, will diffuse through biological fluids, 15 so if it is -- if a molecule such as Fluoxetine -- 16 such as serotonin, is released at some particular 17 site, if it were not actively transported back 18 up, it would in time diffuse out away from that 19 site. 20 Q. How much time after it's 21 released into the site? 22 A. Well, there's -- I don't know 23 the answer. There would be physical laws which 24 would influence the rate at which it diffuses and Page 441 1 there probably would be some rate in microliters 2 per second or something of that sort, but I don't 3 know that because that's not considered very 4 relevant to serotonin -- to an understanding of 5 serotonin physiology. 6 Q. When you say it's not 7 considered relevant, considered relevant by who? 8 A. By those people who are 9 investigating serotonin physiology. 10 Q. People outside of Lilly, as 11 well as at Lilly? 12 A. Yes. 13 Q. When you say extracellular, do 14 you mean outside the, for instance, serotonin 15 neuron? 16 A. Yes, I do. 17 Q. So it's that serotonin that 18 has been released by the neuron? 19 A. Yes. 20 Q. Is it fair to say that the 21 reason that you believe that the concentration of 22 serotonin after Fluoxetine administration remains 23 the same in the synaptic cleft is because it 24 remains the same in the brain tissue that's Page 442 1 studied? 2 A. That's inaccurate. Serotonin 3 concentration in the synaptic cleft does not 4 remain the same. Serotonin concentration in the 5 synaptic cleft increases as a result of blocking 6 the uptake site with Fluoxetine. 7 Q. How do you know that? 8 A. By measurement of the amount 9 of extracellular serotonin and by the various 10 functional changes that occur as a consequence of 11 blocking the uptake carrier. 12 Q. The measurement of 13 extracellular serotonin in the synaptic cleft 14 itself? 15 A. As I explained when we 16 discussed this earlier, there are -- I may not 17 have explained in complete detail, so I will do 18 that now. There are different ways of -- by 19 which the extracellular concentration of 20 serotonin has been shown to be increased after 21 Fluoxetine administration, and these have evolved 22 as technology has advanced for being able to make 23 these measurements. The first measurement was -- 24 involved a fleurometric technique by Mark Geyer, Page 443 1 G-E-Y-E-R, and colleagues at the University of 2 California in San Diego, who used a technique 3 which they called abbreviated fading, 4 F-A-D-I-N-G, and what they showed is that drugs 5 like monoamine oxydase inhibitors increased the 6 amount of serotonin inside of neurons, whereas 7 Fluoxetine increased the amount of serotonin 8 outside the neuron in the synaptic cleft. The 9 next technique to be applied was a technique 10 called -- 11 Q. Let me stop you there real 12 quick. That technique specifically showed that 13 there was an increase of serotonin at the 14 synaptic cleft -- in the synaptic cleft? 15 A. In the extracellular fluid. 16 Q. And the extracellular fluid is 17 limited specifically to the synaptic cleft? 18 A. No. The extracellular fluid 19 is everywhere outside the cell. 20 Q. So they measured the increase 21 in serotonin in the fluid, generally, outside the 22 cell. 23 A. Yes. 24 Q. There is no way of knowing if Page 444 1 that fluid was localized -- or that the serotonin 2 was localized in any way at the synaptic cleft? 3 A. It certainly would not all be 4 within the synaptic cleft, but that would be the 5 initial site of its release, so you would expect 6 that that would be among the places where it 7 would be increased. 8 Q. That's an assumption made 9 because of the concentration found in the fluid 10 itself? 11 A. It may be, since I'm not an 12 expert in that technique, I couldn't comment on 13 the ability with which those investigators were 14 able to distinguish between a synaptic cleft 15 concentration versus another extracellular 16 concentration, I don't know. 17 Q. Okay. I'm sorry, go ahead. 18 A. The second technique was 19 called in vivo voltemetry and it was pioneered by 20 Ralph Adams and his colleagues at the University 21 of Kansas. And he, I believe, while he was on 22 sabbatical in the UK, collaborated in a study in 23 which the investigators showed that a voltametric 24 signal, which they had several pieces of evidence Page 445 1 to suggest was serotonin, was increased in 2 response to Fluoxetine. The third -- 3 Q. Wait, again. 4 MR. HARRIS: Objection. Let him 5 finish answering the question. 6 MS. ZETTLER: I will, I just want to -- 7 instead of going back and rehashing this all 8 over, we might as well get it over with while he 9 is in the process of explaining it. 10 MR. HARRIS: Same objection. 11 Q. With that second method that 12 you just described, is there any way to 13 differentiate between concentrations of serotonin 14 in the synaptic cleft as opposed to the 15 concentration with another extracellular fluid? 16 A. No. As I think I said 17 yesterday, the size of a synaptic cleft is 18 smaller than the size of a probe that one would 19 use to measure the extracellular concentration. 20 So you could not insert a probe directly into a 21 synaptic gap. 22 Q. Okay. 23 A. The third line of evidence was 24 a result of studies using push-pull cannula Page 446 1 technique, which I believe I did describe 2 yesterday. And this is the most quantitative of 3 the techniques that I mentioned so far and it 4 involves the withdrawal of a small amount of 5 extracellular fluid from some particular site in 6 the brain. And investigators at Indiana 7 University Medical Center showed that Fluoxetine 8 administration caused a several fold increase in 9 extracellular concentrations of serotonin using 10 that technique. 11 And the fourth and final 12 technique, which is the newest and I think far 13 and away the most elegant certainly completed 14 quantitative technique, is the brain 15 microdialysis method. And that has been shown by 16 several groups of investigators, including 17 ourselves, Ken Perry and my laboratory, 18 Fluoxetine has been shown to cause a several fold 19 increase in extracellular serotonin in several 20 regions of the rat brain that has been studied. 21 Q. And that last technique, 22 again, can you in any way differentiate between 23 the concentration of serotonin at the synaptic 24 cleft and that in the fluid generally? Page 447 1 A. No. I think what has been 2 measure is extracellular fluid, and as I 3 mentioned yesterday, there are serotonin neurons, 4 in fact, that don't even make synaptic contact 5 with other neurons. 6 Q. Okay. And the third method, 7 you said, would be true as far as measuring how 8 much is in the -- what the concentration in the 9 actual cleft is, would be true of the third 10 method, the push-pull? 11 A. That's correct. 12 Q. What's a synaptosome? 13 A. A synaptosome is a small 14 particle which should be thought of essentially 15 as a pinched off nerve ending. When one 16 homogenizes brain tissue, the endings of nerves 17 actually pinch off into little sacs which are 18 called synaptosomes and they retain many of their 19 functions, including the ability to take up 20 monoamines. So a synaptosome from a serotonin 21 nerve terminal would retain the ability to take 22 up serotonin. A synaptosome from a dopamine 23 nerve terminal would retain the ability to take 24 up dopamine. And so preparations of the Page 448 1 synaptosomes are used in the study of the 2 transport of each of these transmitters. 3 Q. Just -- can a synaptosome 4 still create or release serotonin? 5 A. Yes, they can release 6 serotonin. 7 Q. Is that because yesterday, I 8 think, you said that a serotonin neuron can 9 release serotonin because of an electrical pulse 10 that it is receiving from another neuron or from 11 an electrical pulse that's created spontaneously? 12 A. Yes. 13 Q. So because it can create these 14 spontaneously, they can still release serotonin, 15 the synaptosomes? 16 A. Well, the synaptosomes 17 wouldn't be releasing serotonin, wouldn't, 18 because it's only a small part of the serotonin 19 nerve terminal, it wouldn't generate action 20 potentials and actually release serotonin by 21 itself, but you can do things to those 22 synaptosomes which will trigger the release, such 23 as add drugs like fenfluramine which release 24 serotonin, or add high concentrations of Page 449 1 potassium, which would release that serotonin. 2 So it is possible to study release from the 3 synaptosomes, just the same as one can study 4 uptake by the synaptosomes. 5 Q. How does a neuron fire 6 spontaneously? 7 A. Well, I don't know that I can 8 explain the mechanics of that very well. I think 9 what I was referring to yesterday, is that a 10 neuron may undergo a very regular pattern of 11 firing that appears to be not in response to a 12 signal from some other neuron, but when other 13 neurons then alter their input to that, this may 14 be speeded up or slowed down. 15 Q. Do you know Doctor Peter 16 Burgen? 17 A. Yes. 18 Q. Can you tell me -- 19 A. I know who he is, I don't know 20 him personally. 21 Q. How do you know Doctor Burgen 22 or who he is? 23 A. I have read -- well, I have 24 seen his -- a book that he wrote. Page 450 1 Q. Which book? 2 A. Called Toxic Psychiatry, I 3 believe, or something like that. 4 Q. Have you read the book? 5 A. I read it for about ten 6 minutes perhaps, in a bookstore, I didn't 7 complete it. 8 Q. Why not? 9 A. The book store clerk was 10 encouraging me to either buy something or leave. 11 Q. Does that happen a lot? 12 MR. MYERS: You don't have to answer 13 that. 14 MR. HARRIS: Buy books or getting run 15 off? 16 MS. ZETTLER: My mother is like that 17 too, they almost have to throw her out of 18 bookstores. 19 Q. Have you ever been in contact 20 with Doctor Burgen? 21 A. Yes. I wrote him a short 22 letter as a result of having read that book, 23 parts of that book. 24 Q. Parts of the book? Page 451 1 A. Yes. 2 Q. The ten minutes in the 3 bookstore? 4 A. Yes. 5 Q. When did you write him a 6 letter? 7 A. Well, I remember that I read 8 the book while I was Christmas shopping and that 9 must have been -- that perhaps was in 1992, so I 10 probably wrote the letter shortly thereafter. 11 MR. HARRIS: You didn't purchase the 12 book for your children, correct? 13 MS. ZETTLER: As a gift for somebody? 14 Q. Why did you write to Doctor 15 Burgen? 16 A. Because it appeared that he 17 had misunderstood and misinterpreted some -- 18 because he mentioned my name in the book and that 19 in so doing, he had misinterpreted or 20 misunderstood the meaning of some of the research 21 results that I had published. 22 Q. Which research results? 23 A. The results that have to do 24 with the decrease in serotonin turnover that Page 452 1 occurs in response to giving Fluoxetine. 2 Q. Did you ever speak with Doctor 3 Burgen? 4 A. No, I don't think so. 5 Q. Did he write back to you? 6 A. No, he didn't. 7 Q. Did you write to him again? 8 A. No. 9 Q. How come, why not? 10 A. I had nothing more to say. 11 Q. Do you still have a copy of 12 that letter -- did you keep a copy of that letter 13 in your files? 14 A. I would not be surprised, but 15 I don't know specifically, I don't recall I've 16 ever had the occasion to look for it, so I don't 17 know. 18 Q. Did anybody ask you to write 19 to Doctor Burgen? 20 A. No. 21 Q. Did you tell him you objected 22 to having your name in the book? 23 A. No, I don't believe I said 24 that. Page 453 1 Q. Have you been told that you're 2 going to testify in Fentress case in Kentucky, in 3 Louisville? 4 A. I don't think I've been told 5 that, but it wouldn't come as a complete 6 surprise. 7 Q. Have you been told or asked by 8 anyone to testify at any Prozac trial? 9 A. I have been told of the 10 possibility of that, but I have not testified at 11 any trial. 12 Q. Have you been asked to testify 13 at any criminal trial where the use of Prozac is 14 being blamed for a murder or a violent-aggressive 15 act? 16 A. No. 17 Q. Have you consulted with any 18 prosecuters in any such trials? 19 MR. MYERS: Wait a second, let me -- 20 MR. HARRIS: To the extent that Texas 21 enjoys a joint defense privilege, we would assert 22 the attorney-client privilege and work product 23 privilege. Under 502B of the Texas Rules of 24 Civil Procedure, co-defendants enjoy the Page 454 1 attorney-client privilege. 2 MS. ZETTLER: So you are saying you 3 are co-defendants with the prosecuter in Texas? 4 MR. HARRIS: You asked was he going to 5 testify in any suit, and yes, I am a co-defendant 6 with Lilly in Texas. 7 MS. ZETTLER: Well, that's a few 8 questions ago now, Bob. 9 MR. MYERS: He can answer the 10 question. 11 A. Now can you restate the 12 question? 13 Q. Have you talked to any or 14 consulted with any prosecuters in any criminal 15 cases where the defendant is asserting a Prozac 16 defense? 17 A. Not to my knowledge, no. 18 MR. HARRIS: Just for the record, 19 Nancy, we also have a case in Texas that says 20 that an objection that follows after several 21 questions is timely. 22 Q. Is it possible that 23 Norfluoxetine could prevent the binding of 24 Fluoxetine at an uptake site? Page 455 1 A. Well, Norfluoxetine binds to 2 the same uptake site that Fluoxetine binds to, so 3 there would be -- it's the same for those two 4 agents as it is for serotonin, that the presence 5 of anything else which has affinity for that site 6 will limit the binding of -- let me start again. 7 The presence of a second or third agent that has 8 affinity for that site would limit the binding of 9 the first agent. 10 Q. Okay. Would that account for 11 somebody who has been off of Fluoxetine for two 12 or three days still testing at therapeutic levels 13 of Fluoxetine in the blood? 14 MR. MYERS: Let me object to the form. 15 That may be a clinical question or require a 16 clinical judgment. If you can shed some light on 17 it, go ahead. 18 A. If I have understood the 19 question correctly, my answer would be that I 20 think the -- I don't think the affinity of either 21 Fluoxetine or Norfluoxetine at the serotonin 22 uptake site is a significant determinate of their 23 plasma half-life. I think the duration of their 24 plasma half-life is a function of the rate at Page 456 1 which they're metabolized, probably in the liver, 2 and that it is probably not influenced reportedly 3 by their affinity for the serotonin transporter. 4 Q. Yesterday, you said that you 5 refereed for scientific journals about once a 6 week? 7 A. Yes. 8 Q. Which journals, or journal? 9 A. I believe at last count about 10 sixty-two or sixty-three journals. 11 Q. You don't referee once a week 12 for each of those journals, do you? 13 A. No. 14 Q. Because you're a referee for 15 sixty some odd journals, you end up looking at 16 papers once a week? 17 A. Yes, that is right. 18 Q. Any psychiatric journals? 19 A. Yes. 20 Q. Which ones? 21 A. I don't know that I can 22 remember for certain, I think the American 23 Journal of Psychiatry. I don't trust my memory, 24 some of those sixty some odd journals would Page 457 1 include psychiatric journals. 2 (PLAINTIFFS' EXHIBIT 14 WAS 3 MARKED FOR IDENTIFICATION AND 4 RECEIVED IN EVIDENCE.) 5 Q. Have you had a chance to look 6 at Exhibit 14? 7 A. Yes, I have. 8 Q. Have you seen this before? 9 A. I'm sure I have. It's a 10 report from the Fluoxetine -- the minutes of a 11 Fluoxetine project team meeting in July, 1978. 12 Q. Are you the author of that? 13 A. Yes, I am. 14 Q. If you could look at Exhibit 15 11. Exhibit 11 reflects minutes from a meeting 16 that was held approximately one week before the 17 meeting minutes of the meeting that was reflected 18 in Exhibit 14, correct? 19 A. No, that is not correct. 20 MR. MYERS: This is 1979, that's 1978. 21 Q. I'm sorry, okay. So it's 22 about a year earlier, the meeting is about a year 23 earlier, Exhibit 14. 24 A. These are reports from two Page 458 1 separate project team meetings, one was in 1978 2 and one was in 1979. 3 Q. So, Exhibit 14 was a year 4 earlier? 5 A. Yes. 6 Q. The first paragraph of Exhibit 7 14 talks about three trials in depression having 8 started and another one about to start, correct? 9 A. Yes. 10 Q. These are still open label 11 studies, as far as you know? 12 A. Well, that is not specifically 13 stated in these minutes, but from what is said a 14 year later, it's apparent that they were. 15 Q. The first paragraph of the 16 second page at the top states, none of the eight 17 patients who completed the four week treatment 18 showed distinct drug-induced improvement, 19 correct? 20 A. Yes. 21 Q. Is that drug-induced, meaning 22 Fluoxetine induced? 23 A. Yes. 24 Q. And another patient had Page 459 1 improved, but the improvement started during the 2 placebo period before drug treatment was started, 3 correct? 4 A. Yes. 5 Q. The next paragraph starts out 6 talking about a fairly large number of reports of 7 adverse reactions, do you see that? 8 A. Yes. 9 Q. Is this your opinion or is 10 this information related that was discussed 11 during the meeting? 12 A. It's information that was 13 discussed during the meeting. 14 Q. Who would have given you that 15 information at that time? 16 A. Whoever was the clinical 17 monitor at that time, and among the addressees, 18 the person that that would be, would be Doctor 19 Shulman. 20 Q. Shulman? 21 A. Yes. 22 Q. Okay. That second paragraph 23 on the second page of the exhibit goes on to talk 24 about different types of adverse reactions Page 460 1 reported, correct? 2 A. Yes. 3 Q. At the bottom of that 4 paragraph it says, another depressed patient 5 developed psychosis, manifested by paranoid 6 delusions while taking Fluoxetine. Do you see 7 that? 8 A. Yes. 9 Q. Also it goes on to say, 10 akathisia and restlessness were reported in some 11 patients. Do you see that? 12 A. Yes. 13 Q. To your knowledge, was any 14 determination made as to whether or not these 15 adverse reactions were as a result of taking 16 Fluoxetine? 17 A. I don't think I know what kind 18 of determination you would be thinking about. 19 Q. Any determination of whether 20 or not it was -- there was a causal relationship 21 between the use of Fluoxetine and say, for 22 instance, this patient developing psychosis and 23 manifesting it by paranoid delusions? 24 A. I don't know how one would Page 461 1 determine that in an individual patient, short of 2 repeating the treatment at some later time, and 3 so far I know that was not done. 4 Q. Why not? 5 A. I could not answer that, 6 having not been involved in the design of those 7 clinical studies or their execution. It may have 8 been -- I could only speculate. 9 MR. MYERS: Don't do that. 10 Q. Do do you understand the term 11 rechallenge, rechallenging a patient? 12 A. I think I do, but if you have 13 something specific in mind, I'd appreciate it. 14 Q. My understanding of what it 15 means to rechallenge a patient is, say, for 16 instance, using this person who developed 17 psychosis, say that this person was not suffering 18 from psychosis, they were placed on Fluoxetine, 19 they developed psychosis and then were taken off 20 of Fluoxetine and the psychosis disappeared, 21 okay. Rechallenging would then be to place them 22 back on the Fluoxetine to see if the psychosis 23 reappeared. Is that a fair description of 24 rechallenging? Page 462 1 A. That would be a reasonable 2 description, yes. 3 Q. Is that what you mean when you 4 say, short of -- 5 A. Yes. That is what I meant by 6 one approach to ascertain if an effect was due to 7 a drug. 8 Q. As a biologist, do you 9 consider that a scientifically valid method of 10 testing whether or not there is a relationship 11 between a particular event and a use of a 12 particular drug? 13 A. As a scientifically valid 14 method, it is -- I suppose, the short answer 15 would be yes. 16 Q. Okay. Are you aware that the 17 FDA and in 1990, asked Lilly to at least consider 18 doing a rechallenge study on patients who had 19 become suicidal while taking Fluoxetine? 20 MR. MYERS: I object to the form, in 21 that it mischaracterizes the activity between 22 Lilly and the FDA. But if you know, Doctor, tell 23 her. 24 MS. ZETTLER: It does not Page 463 1 mischaracterize anything, unless you would like 2 to say that they asked them to do a rechallenge 3 study. 4 MR. MYERS: If I'm wrong, my objection 5 will be overruled, and if I'm not, it won't be. 6 A. Because I was not involved in 7 the communication between the medical division 8 and the FDA, I would have no way of knowing that. 9 If I heard that, I don't specifically recall 10 having heard that. 11 Q. Are you aware that a 12 rechallenge protocol to rechallenge patients who 13 had become suicidal on Fluoxetine to see if they 14 became suicidal again, was in fact put together 15 by Lilly and submitted to the FDA for approval? 16 MR. MYERS: I object to the form, 17 insofar as it mischaracterizes what the protocol 18 was. But if you know, tell her. 19 A. Again, that's not the sort of 20 thing that I was involved in and so I don't have 21 specific knowledge or recollection of that. 22 Q. Why were cerebrospinal fluid 23 samples taken from patients that participated in 24 Phase 2 projects as reflected on the last Page 464 1 paragraph on the second page of Exhibit 14? 2 A. The purpose, as I recall, was 3 to ascertain if the doses of Fluoxetine being 4 used were sufficient to inhibit serotonin uptake. 5 The expectation being that if they were, there 6 would be a decrease in cerebrospinal fluid levels 7 of 5HIAA. 8 Q. What were the doses that were 9 being administered to these patients? 10 A. I don't see that recorded in 11 the minutes. 12 Q. What were the results of the 13 analysis of the cerebrospinal fluid, at least as 14 reflected in this exhibit? 15 A. Well, according to this 16 report, one patient showed a decrease in 5-HIAA 17 from thirty-nine to thirty-one nanograms per 18 milliliter, and another a decrease from 19 twenty-seven to fifteen and nanograms per 20 milliliter. 21 Q. Would that -- are you done? 22 I'm sorry. 23 A. One patient showed a reduction 24 in the accumulation of 5-HIAA induced by Page 465 1 probenecid, which is a drug that decreases the -- 2 or inhibits the transport of 5-HIAA out of the 3 brain. 4 Q. Okay. As far as those people 5 on Fluoxetine that -- whose 5-HIAA levels 6 decreased, would you expect them, under your 7 theory of serotonin neurotransmission, to exhibit 8 signs of decreased depression? 9 A. The -- there are two separate 10 and distinct facts which need to be laid out, I 11 think. One is that in some depressed patients 12 who are not being treated with any drug, there 13 can be a reduced concentration of 5-HIAA in the 14 cerebrospinal fluid and the interpretation that 15 is made from that finding is that there was a 16 decreased amount of serotonin being formed and 17 released and that might possibly have been 18 related to the disease. A second fact is that 19 when one gives a serotonin uptake inhibiting 20 drug, there is a decrease in serotonin turnover, 21 one manifestation of which is a decrease in 22 5-HIAA concentration as measured in animals, in 23 brain tissue. But, of course, one cannot measure 24 that in humans in brain tissue; therefore, the Page 466 1 measurement would be in the cerebrospinal fluid. 2 So, the change in 5-HIAA after a drug such as 3 Fluoxetine is given, if there is a decrease in 4 5-HIAA that would indicate that serotonin uptake 5 has been inhibited, and then as a consequence of 6 that inhibition, one might expect that there 7 would be alleviation of the depressive symptoms. 8 Q. And these -- do the levels to 9 which these patients, these two patients' 5-HIAA 10 decreased, would that indicate to you that there 11 was inhibition of uptake resulting from the 12 administration of Fluoxetine occurring? 13 A. Yes, that would be the 14 interpretation. 15 Q. Do you know if either one of 16 these patients showed signs of drug-induced 17 improvement? 18 A. No, I do not know that. 19 Q. Why would their levels -- 20 their metabolite levels decrease and they would 21 not show increased improvement? 22 MR. MYERS: Let me object to the form. 23 He didn't say they didn't, he said he didn't 24 know. Page 467 1 MS. ZETTLER: I'm asking him why 2 wouldn't they, if they didn't. 3 A. I think -- 4 Q. Assuming that the reduce in 5 the 5-HIAA meant that serotonin was not being 6 retaken up into the neuron? 7 A. The -- it was certainly known 8 by the investigator treating the patients, 9 whether those patients improved or not. It 10 wasn't recorded in the minutes and it may not 11 have been known to the project team, at that 12 time, because the information might not have yet -- 13 a study, having not been completed, the 14 information might not yet have been transmitted 15 by the investigators, so that the question of 16 whether those patients improved or not 17 clinically, is simply one that I don't know the 18 answer to. 19 Q. Well, it's hard for us to tell 20 what studies they came from because the names of 21 these study sites it looks like or the doctor's 22 names have been blacked out, correct? 23 MR. MYERS: They have been, but he has 24 no responsibility for that, that's my Page 468 1 responsibility. 2 MS. ZETTLER: I didn't suggest that, 3 Larry, I'm not suggesting that. I'm asking him a 4 simple question. 5 MR. MYERS: You shouldn't even 6 question him about redactions, because he doesn't 7 have anything to do with them, that's my 8 responsibility. 9 MS. ZETTLER: I have a right to ask 10 him whether or not we can interpret what is said 11 in this document based on whether or not things 12 have been redacted, and you know it. 13 MR. MYERS: That wasn't the question. 14 MS. ZETTLER: Yes, it was the 15 questions. 16 MR. MYERS: What was the question? 17 MS. ZETTLER: We'll read the question 18 back. This time could you really listen to it, 19 so you know what I'm asking for a change, instead 20 of jumping to conclusions? 21 (THE COURT REPORTER READ BACK THE 22 REQUESTED TESTIMONY.) 23 Q. Can you tell from looking at 24 this whether the names of the doctors or the Page 469 1 names of the study sites being blacked out, were 2 these studies -- what studies these were related 3 to or what studies these were? 4 A. I don't think knowing the 5 names of the doctor would help in any way to know 6 whether an individual patient improved or not. 7 Q. We could find out whether or 8 not these studies in the bottom -- that we talked 9 about at the bottom of the page, are included in 10 the eight patients who completed the four week 11 study, for instance, correct, none of whom showed 12 any, at least, improvement. 13 MR. HARRIS: I' m going to object, 14 only because this requires this witness to assume 15 and speculate wildly. 16 MS. ZETTLER: Sure, because all the 17 names are blacked out and you can't tell. 18 MR. HARRIS: And I'm going to object 19 to that as well. 20 MR. MYERS: If you know, Doctor 21 Fuller, tell her, if you don't know, tell her 22 that. 23 A. To the best of my knowledge 24 and judgment, knowing the names of the Page 470 1 investigators would not help one know whether an 2 individual patient had improved or not. 3 Q. Well, it sure would help you 4 to take a look to find the study records at Lilly 5 and find out if that patient improved, wouldn't 6 it? 7 A. The question is, would it help 8 you search through the records and find out if 9 this patient improveed? Yes. 10 Q. Can you tell from this exhibit 11 whether or not the patients from which 12 cerebrospinal fluid samples were taken, discussed 13 at the bottom of the page, were members of the 14 eight patients group who completed the four week 15 treatment? 16 A. No, you cannot tell. 17 Q. And then the next page, the 18 last full paragraph of the page talks about a 19 school of thought under which a subgroup of 20 depressed patients were thought to be identified 21 by measuring 5-HIAA concentration in the 22 cerebrospinal fluid, do you see that? 23 A. Yes. 24 Q. Do you agree with that? Page 471 1 A. Yes. I agree that was a 2 school of thought. 3 Q. Do you agree that that was a 4 possibility or is a possibility, identifying the 5 subgroup of depressed patients deficient in 6 serotonergic function? 7 A. That appears to be a 8 possibility, yes. 9 Q. Has Lilly, to your knowledge, 10 ever done such studies to determine whether or 11 not it is possible to identify a subgroup of 12 depressed patients who are deficient in 13 serotonergic function? 14 A. I think there may have been 15 Lilly sponsored studies in which 5HI levels were 16 measured in the cerebrospinal fluid, studies 17 other than this one. 18 Q. Do you know who conducted 19 those studies? 20 A. I know there are -- no, I 21 don't. 22 Q. Do you know if the results of 23 those studies were published by Lilly or anybody 24 else who has conducted such studies? Page 472 1 A. No , I don't remember. 2 Q. Is there somewhere you would 3 be able to find out if Lilly has published such a 4 study? 5 A. The way I would find out is 6 using the literature search system that I use, 7 called Paper Chase, and I would enter Fluoxetine, 8 and I would enter cerebrospinal fluid, and I 9 would enter 5-Hydroxyindoleacetic acid, and I 10 would press the button to show me all the papers 11 in which those three terms have been used. 12 Q. Is there a librarian at Lilly 13 that maintains the medical literature that has 14 been published by Lilly personnel? 15 A. I do not know. 16 Q. After you did your search on 17 Paper Chase, would you just read the publication 18 if there was one right off the screen or print it 19 out on the computer, or would you go get a hard 20 copy from a medical library or somewhere at 21 Lilly? 22 A. I would probably be able to 23 read the abstract directly off the screen and if 24 the information I needed was not contained in the Page 473 1 abstract, then I would need to go somewhere and 2 get a copy of the paper. 3 Q. Does Lilly maintain a medical 4 library? 5 A. Yes. 6 Q. Do they have publications -- 7 periodical publications like journals and things 8 like that in the library? 9 A. Yes. 10 Q. On the third page of the 11 exhibit, above the paragraph titled toxicology, 12 it talks about a study on -- 13 A. I'm sorry, you're on the 14 fourth page? 15 Q. Is it the fourth page? I'm 16 sorry, you're right, the last page of the 17 exhibit. Actually, this discussion that starts 18 on the page previous talks about Phase 1 clinical 19 studies where Doctor Lemberger gave 5-HTP in 20 combination with Fluoxetine to human volunteers? 21 A. Yes. 22 Q. On the next page at the bottom 23 of the paragraph, it says, this work was 24 completed before the FDA questioned the protocol Page 474 1 and some further clinical work may be done when 2 their questions are answered. What do you mean 3 by the FDA questioned the protocol? 4 A. I do not remember from 1978 5 what that would have referred to. 6 Q. Do you know if that protocol 7 was submitted to the FDA before Doctor Lemberger 8 started working on it, working on the study? 9 A. Because I believe that is 10 always done, I believe it would have been, yes. 11 Q. Wouldn't they have questioned 12 the protocol before work was completed on it? 13 MR. MYERS: Let me object to the form 14 in that you call upon him to speculate what the 15 FDA would have done at any given point in time 16 and that is speculation. If you know, tell her. 17 Q. Do you know if some questions 18 were raised about the protocol as a result of the 19 results of Doctor Lemberger's studies? 20 A. No. As I testified, I don't 21 know what the questions were, so I couldn't guess 22 at what they were about. 23 MR. HARRIS: Just for purposes of 24 housekeeping, that document that you have had him Page 475 1 testify from, can we have those attached to his 2 deposition? 3 MS. ZETTLER: Sure. That's all I have 4 for right now, Doctor. Thanks. 5 * * * * * * * * * * 6 CROSS EXAMINATION 7 BY MR. HARRIS: 8 Q. I've got a few questions, if 9 you will bear with me. First off, Doctor Fuller, 10 I want to thank you for the elegant and 11 exhaustive education of neuron transmission and 12 neuron reception. 13 A. You're welcome. 14 MR. HARRIS: Larry, we have the same 15 agreement to this witness, he's not going to 16 issue any medical opinion? 17 MR. MYERS: He's not going to give any 18 medical opinions. 19 MR. HARRIS: With regards to standard 20 of care in Texas or Dallas County. 21 MR. MYERS: Correct. 22 MR. HARRIS: All right. 23 Q. Doctor Fuller, do you know all 24 the causes for suicidal ideation? Page 476 1 A. Do I know all the causes? 2 Q. Yes. 3 A. No, I don't. 4 Q. Are you competent to render an 5 opinion on the causes of suicidal ideation? 6 A. I don't think so. 7 Q. Do you know all the causes for 8 suicide in humans? 9 A. No, I do not. 10 Q. Are you competent to render an 11 opinion about the causes of suicide in humans? 12 A. Certainly not any sort of 13 informed medical opinion, no. 14 Q. That is exactly what I want to 15 talk to you about. The -- just for purposes of 16 the record, Fluoxetine, if I can pronounce it 17 right, Fluoxetine Hydrochloride is Prozac, is it 18 not, Doctor? 19 A. Yes, it is. 20 Q. And that was approved in what 21 year by the FDA? 22 A. It was approved at the very 23 end of 1987. 24 Q. For treatment of what disease? Page 477 1 A. Of mental depression. 2 Q. To your knowledge, Doctor, are 3 there any -- did Lilly publish any medical 4 bulletins, journals, studies, findings, between 5 the years of 1987 and 1991, that would suggest 6 that there was a causal link between the use of 7 Prozac and suicidal ideation or suicide in 8 humans? 9 A. No, not to my knowledge. 10 Q. Did you personally? 11 A. No, I did not personally. 12 Q. During the period of 1987 to 13 1991, did Lilly publish any documents, articles, 14 medical treatise, that would suggest that a 15 physician should administer a sedative to a 16 patient who was ingesting Prozac? 17 A. That is not something I am 18 likely to know. To my knowledge, the answer 19 would be no. 20 Q. You did not personally? 21 A. I did not personally. 22 Q. That you're sure of? 23 MS. ZETTLER: Under your Texas rule, 24 I'm going to make an objection to the extent that Page 478 1 you have to define what publication is, if it's a 2 journal or -- 3 MR. HARRIS: No, I don't. 4 Q. Doctor, what do you mean by 5 publication? 6 A. I interpret your question to 7 mean any sort of publication in a medical journal 8 or anything comparable to that. 9 Q. How about memoranda or any 10 other document, either you or Lilly personally 11 issued? 12 A. My answers would be the same. 13 MR. HARRIS: Thank you, Doctor. 14 MS. ZETTLER: Are you talking strictly 15 here in the United States or outside the United 16 States, also? 17 MR. HARRIS: Anywhere. 18 Q. (BY MR. HARRIS) Is your 19 answer still the same, Doctor? 20 A. I would be even less likely to 21 know what happened outside the United States, but 22 to my knowledge, the answer would be the same. 23 MR. HARRIS: Thank you, Doctor Fuller. 24 I will reserve all further questions until time Page 479 1 of trial if you are called. 2 MS. ZETTLER: No further questions. 3 MR. SMITH: No further questions. 4 MS. SEYMOUR: No questions. 5 MS. SPRUILL: No questions. 6 (THE WITNESS WAS EXCUSED.) 7 8 Page 480 1 COMMONWEALTH OF KENTUCKY ) 2 : ss COUNTY OF JEFFERSON ) 3 4 I, MARY KATHLEEN NOLD, A NOTARY PUBLIC IN 5 AND FOR THE STATE OF KENTUCKY AT LARGE, DO HEREBY 6 CERTIFY THAT THE FOREGOING TESTIMONY OF 7 DR. RAY W. FULLER 8 WAS TAKEN BEFORE ME AT THE TIME AND PLACE AS 9 STATED IN THE CAPTION; THAT THE WITNESS WAS FIRST 10 DULY SWORN TO TELL THE TRUTH, THE WHOLE TRUTH, 11 AND NOTHING BUT THE TRUTH; THAT THE SAID 12 PROCEEDINGS WERE TAKEN DOWN BY ME IN STENOGRAPHIC 13 NOTES AND AFTERWARDS TRANSCRIBED UNDER MY 14 DIRECTION; THAT IT IS A TRUE, COMPLETE AND 15 CORRECT TRANSCRIPT OF THE SAID PROCEEDINGS SO 16 HAD; THAT THE APPEARANCES WERE AS STATED IN THE 17 CAPTION. 18 WITNESS MY SIGNATURE THIS THE 24TH DAY OF 19 APRIL, 1994. 20 MY COMMISSION EXPIRES MARCH 10, 1994. 21 22 23 _________________________ MARY KATHLEEN NOLD 24 COURT REPORTER AND NOTARY PUBLIC STATE OF KENTUCKY AT LARGE Page 481 1 2 3 E R R A T A S H E E T 4 5 COMMONWEALTH OF KENTUCKY ) : SS 6 COUNTY OF JEFFERSON ) 7 8 I, RAY W. FULLER, THE UNDERSIGNED 9 DEPONENT, HAVE THIS DATE READ THE FOREGOING PAGES 10 OF MY DEPOSITION AND WITH THE CHANGES NOTED 11 BELOW, IF ANY, THESE PAGES CONSTITUTE A TRUE AND 12 ACCURATE TRANSCRIPTION OF MY DEPOSITION GIVEN ON 13 THE 14 AND 15 DAY OF APRIL, 1994 AT THE TIME AND 14 PLACE STATED THEREIN. 15 PAGE NO. LINE NO. CHANGE REASON Page 482 1 PAGE NO. LINE NO. CHANGE REASON 2 3 4 5 6 7 8 _____________________________ 9 RAY W. FULLER 10 SWORN TO AND SUBSCRIBED BEFORE ME THIS 11 _____ DAY OF __________, 1994. 12 _____________________________ NOTARY PUBLIC, STATE OF 13 KENTUCKY AT LARGE Page 483 1 2 3 4 5 6 Page 484 1 DIRECT EXAMINATION BY MR. SMITH:.....11 2 CROSS EXAMINATION BY MS. ZETTLER:...228 3 REDIRECT EXAMINATION BY MR. SMITH:.........251 4 CROSS EXAMINATION BY MS. ZETTLER:...347 5 PLAINTIFFS' EXHIBIT NO. 1..........157 6 PLAINTIFFS' EXHIBIT NO. 2..........162 7 PLAINTIFFS' EXHIBIT NO. 3..........165 8 PLAINTIFF'S EXHIBIT NO. 4..........183 9 PLAINTIFFS' EXHIBIT NO. 5..........213 10 PLAINTIFFS' EXHIBIT NO. 6..........220 11 (PLAINTIFFS' EXHIBIT 7......317 12 (PLAINTIFFS' EXHIBIT 8......333 13 (PLAINTIFFS' EXHIBIT 9......360 14 (PLAINTIFFS' EXHIBIT 10.....367 15 (PLAINTIFFS' EXHIBIT 11.....376 16 (PLAINTIFFS' EXHIBIT 12.....388 17 (PLAINTIFFS' EXHIBIT 13.....421 18 (PLAINTIFFS' EXHIBIT 14.....458 19 COMMONWEALTH.........481 20 E R R A T A..........482 Page 485