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. DAVID T. WONG 11 DATE: APRIL 13, 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. ) 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 Page 7 1 THE DEPOSITION OF DR. DAVID T. WONG, TAKEN 2 AT THE OFFICE OF BAKER & DANIELS, 300 NORTH 3 MERIDIAN STREET, SUITE 2700, INDIANAPOLIS, 4 INDIANA 46204, ON APRIL 13, 1994; SAID DEPOSITION 5 TAKEN PURSUANT TO NOTICE IN ACCORDANCE WITH THE 6 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 Page 8 1 MARGARET M. HUFF 2 ELI LILLY AND COMPANY LILLY CORPORATE CENTER 3 INDIANAPOLIS, INDIANA 46285 4 ALLISON SPRUILL COUNSEL FOR BEAUMONT NEUROLOGICAL HOSPITAL 5 FRIEND & ASSOCIATES LLP 1301 MCKINNEY #2900 6 HOUSTON, TEXAS 77010 7 KAREN A. SEYMOUR COUNSEL FOR DR. BILLINGSLEY 8 WALLACE, SAUNDERS, AUSTIN, BROWN & ENOCHS 10111 W. 87TH ST. 9 P.O. BOX 12290 OVERLAND PARK, KANSAS 66282 10 ROBERT L. HARRIS 11 COUNSEL FOR NOE NEAVES, M.D. SIFFOLD & ANDERSON, LLP 12 6300 NATIONS BANK PLAZA 901 MAIN STREET 13 DALLAS, TEXAS 75202 Page 9 1 I N D E X 2 3 DEPOSITION OF DR. DAVID T. WONG 4 5 DIRECT EXAMINATION BY MS. ZETTLER 15 6 CROSS EXAMINATION BY MR. HARRIS 313 7 CROSS EXAMINATION BY MR. SMITH 317 8 9 CERTIFICATE 351 10 ERRATA 352 11 EXHIBITS 12 PLAINTIFFS' EXHIBIT NO. 1 30 PLAINTIFFS' EXHIBIT NO. 2 37 13 PLAINTIFFS' EXHIBIT NO. 3 56 PLAINTIFFS' EXHIBIT NO. 4 82 14 PLAINTIFFS' EXHIBIT NO. 5 94 PLAINTIFFS' EXHIBIT NO. 6 177 15 PLAINTIFFS' EXHIBIT NO. 7 232 Page 10 1 MR. MYERS: Before we get started with 2 the resumption of the deposition of Doctor Wong, 3 just for the record I want to do a housekeeping 4 chore. It is my understanding, and I will be 5 happy to be corrected, but there are notices for 6 the deposition of Doctor Wong and the rest of the 7 depositions scheduled in April in the following 8 matters: There is a notice which was issued out 9 of Baker and Daniels for the multi-district 10 proceeding. There is a notice that was issued 11 out of Ed Stopher's office for the consolidated 12 Fentress cases. There is a notice for the Saines 13 case in California. There is a notice for the Di 14 Silvestro case in Illinois, and the Huslig case 15 in Kansas. Mister Smith has issued, as well, 16 notices in his Texas state court cases, which I 17 understand to be Biffle, Welch, Kung, Crossett 18 and Reves. You also issued a notice for the 19 Elizabeth Sanchez case, but I talked to your 20 legal assistant, Amy Kerry, and told her that 21 that case is in the multi-district, so that's 22 sort of a moot point at this point in time. 23 Obviously the Fentress and 24 multi-district and Saines protective orders will Page 11 1 govern. I understand that in Di Silvestro there 2 was a stipulated order entered yesterday, which 3 is in effect a multi-district order. And with 4 respect to the Kansas case, and Mister Smith's 5 state court cases, we have an agreement that the 6 multi-district order shall control and govern the 7 deposition of this witness, and the other 8 depositions this month. 9 Now am I right in the cases that I've 10 recited that there are notices out in these 11 depositions? 12 MS. ZETTLER: As far as I know, you 13 have my cases. 14 MR. MYERS: Is that right? 15 MR. SMITH: As far as I know. 16 MR. MYERS: And we do, in fact, have 17 that agreement with respect to Huslig and your 18 state court cases in Texas. 19 MR. SMITH: Correct. 20 MR. MYERS: And Ms. Court Reporter, 21 we'll get with you at either a break or 22 conclusion to make sure that you have all the 23 current captions. I think you've got most of 24 them, but not all. Page 12 1 MS. ZETTLER: Just a real quick point 2 on the protective order that was issued in the Di 3 Silvestro. I stipulated to the entering of the 4 order, that doesn't necessarily mean I stipulated 5 to Lilly's interpretation of the order regarding 6 any given issue in discovery. 7 MR. MYERS: Right. The order says 8 what it says, and its application, there are 9 provisions in there, in the order, I think, for 10 its application and use of the order, and we'll 11 just let those control. I understand your point. 12 MS. ZETTLER: Okay. 13 MR. MYERS: You can swear him again or 14 he's still under oath, I don't care. 15 MS. ZETTLER: Doctor, do you 16 understand that you're still under oath? 17 THE WITNESS: Yes. 18 MR. HARRIS: Just one comment for the 19 record before we start. 20 MS. ZETTLER: Sure. 21 MR. HARRIS: For your record, I'm 22 Robert Harris appearing for Doctor Noe Neaves in 23 cause number 93-04911-A. My name is Robert 24 Harris with Siffold and Anderson out of Dallas. Page 13 1 To the extent that you've represented we have a 2 multi-district order controlling state litigation 3 for Mister Smith, we have not entered into an 4 agreement that controls the Welch case, and we're 5 under a separate order from Judge Marshall out of 6 Dallas. 7 MR. MYERS: Right. The order which I 8 make reference to is not a scheduling order, but 9 instead a protective order with respect to 10 certain information which may be disclosed in the 11 deposition, and I take it that since you all 12 appeared here today, you are willing, at least 13 for purposes of a discovery protective order, to 14 be bound by that. 15 MR. HARRIS: Yes. 16 MR. MYERS: Is that correct for the 17 other people making appearances today? 18 MS. SEYMOUR: Yes, as far as I know. 19 MR. MYERS: That's fine. 20 MR. SMITH: Would you all please start 21 by reciting part of the protective order? 22 MR. HARRIS: Which part, Paul? 23 * * * * * * * * * * 24 DIRECT EXAMINATION Page 14 1 BY MS. ZETTLER: 2 Q. Doctor, do you understand that 3 all the ground rules that Paul laid out for you 4 last time apply to this deposition too, meaning 5 that if you don't understand my question, ask me 6 to repeat it, and if you want to take a break, 7 things like that? 8 A. I do. 9 Q. Have you read the first 10 portion of your deposition? 11 A. Is that -- 12 Q. The transcript from the first 13 deposition that you gave? 14 A. Yes, I did. 15 Q. Did you find any errors in 16 that deposition that you would like to correct or 17 anything you would like to add or subtract? 18 MR. MYERS: Other than what he's 19 already -- there's already been an errata 20 submitted. 21 MS. ZETTLER: See, I've never seen the 22 errata. 23 MR. MYERS: Well, it's been sent in. 24 And it may be -- I don't know why it is, but it Page 15 1 may be because that deposition was taken by 2 somebody other than Kathy. 3 MS. ZETTLER: Right. 4 MR. MYERS: He did an errata, I don't 5 have it here with me. 6 Q. Your counsel has stated that 7 you filled out an errata sheet when you went 8 through your deposition? 9 A. Yes. 10 Q. Were there any substantive 11 changes to the deposition that you made? 12 A. I don't recall any changes of 13 substance. 14 Q. Was it mostly typographical 15 errors and spellings, things of that nature? 16 A. Yes. 17 Q. Did you do anything in 18 preparation for your deposition today? 19 A. Other than reading the 20 deposition, I have not prepared especially for 21 this meeting. 22 Q. You met with your attorneys? 23 A. Beg your pardon? 24 Q. You met with your attorneys? Page 16 1 A. I just arrived this morning. 2 Q. What time did you get here 3 this morning? 4 A. 8:00. 5 Q. Spent about an hour with them? 6 A. Right. 7 Q. Did you review any documents? 8 A. The document of this 9 deposition, and also my regular scientific 10 literature reading. 11 Q. Okay. Did you do any special 12 scientific reading for the deposition today? 13 A. No. 14 Q. Do you recall what reading you 15 did prior to the deposition that would be 16 applicable to this deposition today? 17 A. The literature is continually 18 developing, it's difficult to differentiate, it's -- 19 like cloning of the transporter for serotonin. 20 Q. Cloning transporter? 21 A. Yes. 22 Q. During the first portion of 23 your deposition, we talked about a couple of 24 different studies that you had read that you Page 17 1 didn't work on, but you had read in the 2 literature, like the Charney study, do you recall 3 that? 4 A. Yes. 5 Q. Did you make an effort to go 6 back and find a copy of that after the first 7 portion of your deposition? 8 A. I apologize, I didn't. 9 Q. Did you make an effort to go 10 back and find any of the studies that we talked 11 about during the last deposition? 12 A. I'm sorry, I didn't. Was that 13 I was asked to do? 14 Q. Not necessarily, I was just 15 wondering if you had gone and done it. Did you 16 ask to review any documents before the deposition 17 today? 18 A. I beg your pardon? 19 Q. Did you ask anybody to let you 20 review documents before today's deposition? 21 A. No. 22 Q. Did you talk to anybody 23 outside of Eli Lilly regarding the first portion 24 of your deposition? Page 18 1 A. No. 2 Q. Do you know a man named Peter 3 Kramer? 4 A. Yes. 5 Q. Who is Peter Kramer? 6 A. He's a psychiatrist. 7 Q. How do you know Doctor Kramer? 8 A. He interviewed me for about an 9 hour. 10 Q. In regards to what? 11 A. In regard to my involvement 12 and discovery of Fluoxetine. 13 Q. When did you meet with Doctor 14 Kramer? 15 A. Precisely the date, I don't 16 recall. 17 Q. Can you give me a general 18 idea? 19 A. Approximately two and a half, 20 two years, two and a half years ago. 21 Q. Where did you meet with Doctor 22 Kramer? 23 A. At Eli Lilly and Company. 24 Q. Was anybody else present Page 19 1 during that meeting? 2 A. Yes. 3 Q. Who? 4 A. Doctor Fuller. 5 Q. Anyone else? 6 A. Doctor Molloy. 7 Q. And who arranged that meeting? 8 A. It was the company's public 9 relation department. 10 Q. Ed West? 11 A. Yes, his department. 12 Q. Do you know if Mister West 13 approached Doctor Kramer or whether Doctor Kramer 14 approached Mister West? 15 A. I'm sorry, I don't know the 16 detail. 17 Q. Were you asked to meet with 18 Doctor Kramer or did you volunteer? 19 A. I was asked. 20 Q. Did you have any objection to 21 meeting with Doctor Kramer? 22 A. I didn't object. 23 Q. Portions of your discussion 24 ended up being published in Doctor Kramer's book, Page 20 1 Listening to Prozac, correct? 2 A. Correct. 3 Q. Did you have a chance to read 4 the manuscript before it was published? 5 A. No. 6 Q. Have you read it since it's 7 been published? 8 A. I did. 9 Q. Do you have any objections or 10 exceptions to what Doctor Kramer wrote as far as 11 what you talked about with him? 12 A. Not particularly. 13 Q. Any clarifications that you 14 would make if you had a chance with Doctor 15 Kramer? 16 A. Not particularly. 17 Q. Do you feel that his rendition 18 of what was discussed in the meeting and your 19 scientific work is accurate in the book? 20 A. I believe so. 21 Q. How about Doctor Fuller or 22 Doctor Molloy, are you aware of any objections 23 that they had to what was written in the book? 24 A. I'm not aware of objections. Page 21 1 Q. Did you discuss the book with 2 Doctors Fuller and Doctor Molloy? 3 A. Just casually. 4 Q. In what way? 5 A. Doctor Kramer's book was 6 interesting and was surprised on my part. 7 Q. You were surprised? 8 A. Yes. 9 Q. Why were you surprised? 10 A. Between the interview and the 11 appearance in the book, never heard anything. 12 Q. So the actual appearing of the 13 book on the shelves was a surprise to you? 14 A. Yes. 15 Q. Were you surprised by anything 16 that was written in the book? 17 MR. MYERS: Let me object to the form, 18 that's a pretty long book and that's an overly 19 broad question for him to comment on the entire 20 contents of the book as opposed to your earlier 21 question -- 22 MS. ZETTLER: I just want to know if 23 he was surprised by anything that was written in 24 the book. Page 22 1 MR. MYERS: Yes, and I object to the 2 form, I think it's overly broad. 3 Q. You can answer it, Doctor. 4 MR. MYERS: Yes, if you can answer it, 5 certainly do so. 6 A. Would you repeat the question 7 again, please? 8 Q. Sure. Did anything that 9 Doctor Kramer wrote in his book surprise you? 10 A. Nothing really surprised me. 11 Q. Are you aware that there is 12 somewhat of a controversy around what Doctor 13 Kramer wrote in his book as far as prescribing 14 Prozac to people who are not suffering from 15 depression? 16 A. My understanding is medical 17 doctors have liberty to do the kind of thing that 18 they see fit to do, so it was not a surprise to 19 me. 20 Q. So would it be fair to say 21 that even though Prozac is only approved for use 22 in depression, it doesn't surprise you that 23 medical doctors are prescribing it for other 24 indications or other reasons? Page 23 1 MR. MYERS: I object to the form. 2 Q. You can answer it, Doctor. 3 MR. MYERS: If you know. 4 A. Again, would you repeat again? 5 MS. ZETTLER: Can you read that back? 6 (THE COURT REPORTER READ BACK THE 7 REQUESTED TESTIMONY.) 8 A. Personally, I prefer that it 9 be mainly used for depression, and like I said, 10 the medical doctors have their free hand in using 11 medication, so I have not been surprised for 12 other uses. 13 Q. Okay. So it doesn't surprise 14 you that doctors would use it for something other 15 than depression since it's on the market? 16 A. Like I said, depression is the 17 only indication that's approved, and that is the 18 intended use of the medication, but other uses of 19 it is not so much a surprise. 20 Q. Other than the meeting that 21 you had with Doctor Kramer, Doctor Fuller and 22 Doctor Molloy, have you ever spoken or 23 communicated in any way with Doctor Kramer? 24 A. No. Page 24 1 Q. Did you ever speak to him on 2 the phone? 3 A. No. 4 Q. How about before the meeting? 5 A. Before which meeting? 6 Q. Before the meeting you had 7 with Doctor Kramer. 8 A. I never met him. 9 Q. Tell me what subjects were 10 discussed during the one-hour meeting you had 11 with Doctor Kramer, Doctor Fuller and Doctor 12 Molloy. 13 A. Pretty much look at the 14 process of -- the discovery process. 15 Q. Anything else? 16 A. Mainly the discovery process. 17 Q. Did the issue of the 18 connection between the use of Prozac and suicidal 19 ideation come up during the meeting? 20 A. I don't recall such 21 conversation. 22 Q. Are you aware of whether or 23 not Doctor Kramer met with anybody else from 24 Lilly regarding his book? Page 25 1 A. I don't recall anybody else. 2 Q. Did anybody, during that 3 meeting, suggest to Doctor Kramer that he contact 4 any clinical investigators for Lilly on Prozac? 5 A. I have no knowledge. 6 Q. Do you recall anybody's name 7 being mentioned during the meeting? 8 A. I don't recall. 9 Q. Are you familiar with a Doctor 10 Ru-Band Lu? 11 A. I'm sorry? 12 Q. Are you familiar with a Doctor 13 Ru-Band Lu? 14 A. Doctor Lu from Taiwan? 15 Q. Yes. 16 A. Yes, uh-huh. 17 Q. How do you know Doctor Lu? 18 A. We met at one of the meetings. 19 Q. When you say one of the 20 meetings, what do you mean? 21 A. He was one of the meeting 22 guests in the company. 23 Q. You met with Doctor Lu at Eli 24 Lilly? Page 26 1 A. Yes. 2 Q. When was that? 3 A. Quite a few years back, I 4 don't recall exactly when. 5 Q. Sometime in 1992? 6 A. Maybe that far back. 7 Q. What was the purpose of your 8 meeting with Doctor Lu? 9 A. Doctor Lu visited the company, 10 mainly was learning about the research program 11 that we have in Lilly, the CNS research. 12 Q. So he spoke with you about the 13 CNS research that you did? 14 A. Yes -- well, it was casually 15 the first meeting we made. 16 Q. Did you have more than one 17 meeting with Doctor Lu? 18 A. Subsequently, in other 19 meeting. 20 Q. When was that meeting? 21 A. Again, I don't recall so many 22 years back. 23 Q. You had Doctor Lu at your 24 house for dinner, didn't you? Page 27 1 A. I did. 2 Q. What was the purpose of that? 3 A. He was visiting, and just 4 another friend from -- because of being -- have 5 the same ancestry or background, and it was very 6 customary for Chinese to have guests. 7 Q. Did somebody at Lilly ask you 8 to entertain Doctor Lu? 9 A. Oh, no. 10 Q. Was it your idea? 11 A. Yes. 12 Q. Prior to the meeting that you 13 had, the first meeting that you had with Doctor 14 Lu at Lilly, had you known Doctor Lu at all? 15 A. No. 16 Q. Are you aware that Doctor Lu, 17 prior to that meeting at Lilly, had done a study 18 where he compared Prozac to Maprotiline and had 19 found there was a higher incidence of suicidal 20 ideation in Prozac as opposed to Maprotiline? 21 MR. MYERS: Before he answers, let me 22 object to the form because I don't think you've 23 accurately characterized whatever it is that 24 Doctor Lu did, and I don't know if your time Page 28 1 sequence was right. But if you know, tell her. 2 A. I wasn't aware of that study. 3 Q. Did you ever become aware of 4 the study? 5 A. Later on. 6 Q. When? 7 A. Upon his visit, only when he 8 was -- 9 Q. During the first meeting at 10 Lilly that you had with him? 11 A. No, much later. 12 Q. After you had him over to 13 dinner? 14 A. That -- no, it was in the 15 daytime, the mention. 16 Q. So you knew about the study 17 when you had him over for dinner? 18 A. Yes. 19 Q. Did you discuss the study with 20 him? 21 A. No. 22 Q. Did anybody at Lilly ask you 23 to try to convince Doctor Lu not to publish his 24 study? Page 29 1 A. Not that I know of. 2 Q. You don't know whether or not 3 somebody asked you to try to convince him? 4 A. I don't recall anybody 5 mentioning that to me. 6 (PLAINTIFFS' EXHIBIT NO. 1 WAS 7 MARKED FOR IDENTIFICATION AND 8 RECEIVED IN EVIDENCE.) 9 Q. Doctor, have you had a chance 10 to review Exhibit Number 1? 11 A. Yes. 12 Q. Did you author this E-mail? 13 A. I'm sorry? 14 Q. Are you the author of this 15 document? 16 A. I did. 17 MR. MYERS: Wait a minute. When you 18 say all of it, do you mean the typewritten part 19 as well as the handwritten part? 20 MS. ZETTLER: Just the E-mail part, 21 not the handwritten part. 22 Q. And it's an E-mail dated 23 February 28th, 1992, correct? 24 A. Yes. Page 30 1 Q. Does that indicate to you when 2 you had Doctor Lu over to your house for dinner? 3 A. Yes. 4 Q. When? 5 A. Exactly which date, I don't 6 remember. After that date they have the meeting 7 with the medical doctors, and that was the 8 evening that I have dinner with him. 9 Q. Okay. Was this E-mail written 10 after your dinner with Doctor Lu? 11 A. Yes, I believe probably the 12 next day. 13 Q. So somewhere around the end of 14 February, 1992? 15 A. Yes. 16 Q. And how long prior to that 17 dinner did you meet with him for the first time, 18 if you recall? 19 A. During this occasion, I only 20 pick him up in the airport. 21 Q. You picked him up at the 22 airport? 23 A. Yes, I did. 24 Q. Was anybody else with you when Page 31 1 you picked him up? 2 A. No. 3 Q. What did you discuss with him 4 during your ride back to Lilly from the airport? 5 A. Normal conversation, casual 6 conversation. 7 Q. Can you give me an idea, give 8 me an example? 9 A. How is he doing, that kind of 10 greetings. 11 Q. Did you speak to him in 12 English or in Chinese? 13 A. Because he's Taiwanese and he 14 has an accent, I did not understand his Mandarin 15 as much as I understand his English, so the 16 conversation was in English. 17 Q. How well does he speak 18 English? 19 A. I can understand him. 20 Q. Did he have any problems 21 understanding you, to your knowledge? 22 A. I don't think so. 23 Q. Who is Doctor Ko? 24 A. It's a lady doctor that came Page 32 1 with him. 2 Q. Was she -- did you pick her up 3 from the airport also? 4 A. I don't recall that they came 5 together. I only took him to the hotel, and then 6 somehow they met within the city. Exactly how 7 they got together, that I don't know. 8 Q. Was Doctor Ko from Taiwan 9 also, to your knowledge? 10 A. Yes. 11 Q. Was she a colleague of Doctor 12 Lu's? 13 A. Yes. 14 Q. Is there a Doctor David Wang -- 15 A. David Wang? 16 Q. -- at Lilly, that you know of? 17 A. Doctor David Wang. 18 Q. Wang, W-A-N-G. 19 A. Oh, yes -- no, Wang is -- 20 David Wong, also, and not David Wang. Both of us 21 have the same first name and last name. 22 Q. So there is a Doctor Wang? 23 A. Yes, W-O-N-G. 24 Q. Another Wong? Page 33 1 A. Uh-huh. 2 Q. I'm concerned about a Doctor 3 Wang. 4 A. No, I don't recall having 5 W-A-N-G. Of course there are people that have 6 David Wang in the city. 7 Q. But not at Lilly as far as you 8 know? 9 A. No. 10 Q. In Exhibit 1, you talk about 11 discussing with Doctor Lu and Doctor Ko that they 12 were glad to come to Indianapolis and discuss 13 their results with Doctor Beasley and Tollefson, 14 right? 15 A. Yes. 16 Q. Does this exhibit refresh your 17 recollection as to whether or not you discussed 18 Doctor Lu's study with him during dinner at your 19 home? 20 A. No. 21 Q. When is it that he would have 22 expressed to you his gladness at being able to 23 discuss his results with Doctor Beasley and 24 Doctor Tollefson? Page 34 1 A. All I gather was pleasant the 2 meeting they have. 3 Q. You were present at that 4 meeting? 5 A. No they had a very pleasant 6 meeting, P-L-E-A-S-A-N-T. 7 Q. Did he tell you that, did 8 Doctor Lu tell you that? 9 A. Yes. 10 Q. Also -- 11 A. I mean it was cordial. 12 Q. Sure. You go on to say in 13 here that they, I assume meaning Doctor Lu and 14 Doctor Ko, indicated to me that they follow the 15 methodology to analyze the data according to that 16 used and published by Doctor Beasley and 17 colleagues. 18 A. Yes. 19 Q. That indicates that you 20 discussed the methodology that they used to -- 21 A. Not methodology, they just 22 mentioned, they state that way, that's all. 23 Q. Do you recall when you had 24 this conversation with Doctor Lu and Doctor Ko Page 35 1 about their using Doctor Beasley's analysis? 2 A. Because Doctor Beasley's paper 3 already just published at that time. 4 Q. But what I'm asking you is 5 when you had this conversation with them. 6 A. When? 7 Q. Right. 8 A. The evening. 9 Q. During dinner at your house? 10 A. I don't know, I think maybe 11 before dinner. 12 Q. Okay. When I say during 13 dinner, I mean when you had them over at your 14 house. 15 A. Yes, that evening. 16 Q. To your knowledge, has Lilly 17 offered to work with Doctor Lu on another study 18 of Fluoxetine? 19 A. I have no knowledge. 20 Q. And it's your testimony that 21 you did not contact Doctor Lu and invite him to 22 come to Indianapolis to meet with Lilly 23 psychiatrists? 24 A. No, I didn't invite him Page 36 1 myself. 2 Q. The first time that you met 3 Doctor Lu was during the first meeting you had 4 with him at Lilly, correct? 5 A. Yes, uh-huh. 6 Q. Did you know who he was prior 7 to that meeting? 8 A. No. 9 Q. Did you know of him at all 10 prior to that meeting? 11 A. No. 12 (PLAINTIFFS' EXHIBIT NO. 2 WAS 13 MARKED FOR IDENTIFICATION AND 14 RECEIVED IN EVIDENCE.). 15 Q. If you could take a look at 16 what has been marked as Exhibit 2. 17 A. Yes. 18 Q. Have you had a chance to read? 19 A. Yes. 20 Q. Have you had a chance to 21 review Exhibit 2? 22 A. Yes. 23 Q. Have you seen this exhibit 24 before, Doctor? Page 37 1 A. Yes, I did, I have. 2 Q. Who is Doctor Lumeng, 3 L-U-M-E-N-G? 4 A. Doctor Lumeng is a medical 5 doctor in Indiana University Medical School. 6 Q. Is he related in any way to 7 Eli Lilly? 8 A. No. 9 Q. The E-mail is dated January 10 23, 1992, correct? 11 A. Yes. 12 Q. And this would have been 13 before the first meeting you had with Doctor Lu? 14 MR. MYERS: When you say the first 15 meeting, what do you mean, you mean this one 16 here? 17 MS. ZETTLER: No. He talked about two 18 different meetings, he said he had him over to 19 his house for dinner, and then he met with him at 20 Lilly. 21 Q. Correct, prior to you having 22 him over to dinner? 23 A. Right. The first meeting at 24 Lilly is way, way back, I don't recall when. And Page 38 1 this is the last meeting that we have in '92. 2 Q. This Exhibit 2 reflects the 3 last meeting that you had in '92? 4 A. Yes. 5 Q. Where did you first meet with 6 Doctor Lu? 7 A. As I said he was a company 8 guest for another occasion, and many years back, 9 I don't recall which year. 10 Q. Was it related to Prozac? 11 A. Even before Prozac become 12 approved, and I don't recall exactly when. 13 Q. Did Doctor Lu ever do any work 14 for Lilly as far as you know? 15 A. As far as I know, no. 16 Q. So the meeting that Exhibit 2 17 discusses in January of 1992, that's a meeting 18 that you attended? 19 A. Yes -- which meeting? 20 Q. The first meeting here, the 21 January -- the one that's talked about in Exhibit 22 2. 23 A. At which meeting that you talk 24 about, in this occasion? Page 39 1 Q. Right. 2 A. I was aware, yes. In meeting, 3 you have to be very precise which meeting. 4 Q. Let me ask it this way: At 5 the time that Exhibit Number 2 was written, 6 January of 1992, were you aware that Doctor Lu 7 had conducted a study that indicated that 8 compared to Maprotiline, Fluoxetine had a higher 9 incidence rate of suicidal ideation? 10 MR. MYERS: Before he answers, let me 11 make the same objection as to the form because I 12 don't think you've accurately characterized what 13 the work was that was done. But if you know, you 14 can answer. 15 A. I didn't aware of that work 16 being done prior to this message. 17 Q. You were not aware? 18 A. No. 19 Q. Did somebody ask you to invite 20 Doctor Lu back to Indianapolis in the early part 21 of 1992? 22 A. Doctor Lu called me and just 23 to discuss about, I believe -- let me see. I 24 don't think Doctor Lu called me, someone called Page 40 1 me, either from Taiwan that contacted me that 2 Doctor Lu have some interest in alcohol drinking -- 3 interest in alcoholism, and Doctor Lumeng 4 developed a colony of rat is preferred drinking 5 alcohol. 6 MR. SMITH: Were they called lawyers 7 there in Taiwan, did they name them lawyers in 8 Taiwan, those rats? 9 MR. MYERS: Doctor Lumeng is the man 10 over at IU. 11 (DISCUSSION OFF THE RECORD.) 12 A. Doctor Lumeng have developed a 13 colony of rat by in-breeding, and the animal 14 become -- by the way they select those animals, 15 and by selecting their behavior to prefer 16 drinking alcohol when the animal be given choice, 17 water or alcohol, and with multiple in-breeding 18 and selection, and the animal upon -- after 19 twenty-six generations of rebreeding and the 20 animal, upon brief presentation of ethanol, which 21 is alcohol, and the animal would drink as much as -- 22 to a level in the animal as much as an individual 23 become drunk. So the interest was that want to 24 talk to Doctor Lumeng about alcoholism. Page 41 1 Q. Okay. So you're saying that 2 Exhibit 2 reflects a meeting that Doctor Lu 3 wanted to set up with Doctor Lumeng so that he 4 could get a hold of some of his rats? 5 A. Yes, communicate, share 6 scientific knowledge about alcohol drinking 7 behavior. 8 Q. And that meeting was a meeting 9 that was held at Lilly in early 1992? 10 A. No, that meeting was held, I 11 only took Doctor Lu to see Doctor Lumeng at the 12 medical center. 13 Q. When, during February of 1992? 14 A. Yes, right, right. 15 Q. That's the only reason that 16 Doctor Lu was here? 17 A. And then after arrival, I 18 realized that the meaning of the message that he 19 have arranged to meet with medical doctors, I 20 didn't even pay attention to, I have no -- 21 because as I alluded to last time, that my focus 22 being in research, basic research, and so it 23 didn't occur to me that there was some kind of 24 interest for Doctor Lu to talk to the medical Page 42 1 doctors until this message from Mister Lin. 2 Q. So in the first full paragraph 3 of Exhibit Number 2, where it talks about Doctor 4 Ko's and Doctor Lu's C.V.s and an invitation sent 5 by Doctor Lumeng, kindly arranged by Doctor Wong, 6 that trip, to your knowledge, at that time, was 7 arranged so he could meet with Doctor Lumeng 8 about the rats, not about the suicide study? 9 A. That's right. 10 Q. Who asked you to set up that 11 meeting? 12 A. Perhaps Mister Lin or -- right 13 now, I don't recall whether it was Doctor Lin -- 14 Mister Lin or Doctor Lu. 15 Q. Who is Mister Lin? 16 A. He's in Lilly, Taiwan. 17 Q. So Doctor Lin may have called 18 you and asked you to arrange a meeting between 19 Doctor Lu and Doctor Lumeng? 20 A. Yes. 21 Q. If it was Doctor Lin -- 22 MR. MYERS: Mister Lin. 23 Q. Mister Lin, I'm sorry. If it 24 was Mister Lin or whoever it was that contacted Page 43 1 you from Taiwan and told you specifically that 2 the meeting was to be held about Doctor Lumeng's 3 rats? 4 MR. MYERS: Let me object to the form 5 only because he said he didn't remember whether 6 it was Mister Lin or Doctor Lu, he said one or 7 the other. 8 Q. So whoever contacted you 9 initially from Taiwan to ask you to help arrange 10 the meeting between Doctor Lu and Doctor Lumeng, 11 told you that the subject of the meeting or the 12 reason for Doctor Lu coming here was purely to 13 discuss rats with Doctor Lumeng? 14 A. Alcoholism, not necessarily 15 rats. 16 Q. Nothing to do with the suicide 17 study? 18 A. I only aware of that after his 19 arrival. 20 Q. After his arrival? 21 A. Yes. 22 Q. Do you know when Doctor Lu 23 arrived after this E-mail was written? 24 A. I'm sorry? Page 44 1 Q. Do you know how long after 2 this E-mail, that's Exhibit 2, that Doctor Lu 3 arrived? 4 A. According to this memo, he 5 arrived in February, a month later. 6 Q. Did you receive a copy of this 7 E-mail when it was written? 8 A. I probably have received that. 9 Q. You didn't receive it after 10 the meeting with Doctor Lu in Indianapolis, did 11 you? 12 A. I'm sorry? 13 Q. You didn't receive it after 14 Doctor Lu came to Indianapolis and met with 15 Lilly? 16 A. Precisely when, I don't 17 recall. 18 Q. The first paragraph of this 19 E-Mail states Doctor Ko and Doctor Lu are coming 20 to Lilly between February 20th and 24th, 1992 to 21 discuss the study results on suicide attempts and 22 Fluoxetine. Do you see that in there? 23 A. Uh-huh. 24 Q. You have to say yes or no for Page 45 1 the record. 2 A. Repeat it. 3 Q. Sure. 4 MR. MYERS: Ask the question again. 5 Q. That's fine. The first 6 paragraph of this exhibit, first full paragraph 7 of this E-mail, specifically talks about Doctor 8 Ko and Doctor Lu coming to Indianapolis the week 9 of February 20th, 1992 to discuss Doctor Lu's 10 study results on suicide attempts and Fluoxetine. 11 Is that a fair assessment of what the first 12 paragraph says? 13 MR. MYERS: She wants to know of 14 that's what it says. 15 A. Yes, it states that. 16 Q. Is it your testimony that you 17 did not see this memo until after Doctor Lu had 18 arrived in Indianapolis? 19 MR. MYERS: Let me object to the form. 20 He answered that, he said he didn't know exactly 21 when he saw it, about two or three questions ago. 22 Q. Is it your testimony that you 23 did not see this memo until after Doctor Lu was 24 already in Indianapolis? Page 46 1 A. I don't recall when I received 2 this document. 3 Q. Are you aware that Doctor 4 Zerbe contacted Doctor Paul Leber at the FDA 5 about Doctor Lu's Maprotiline-Fluoxetine suicide 6 study? 7 A. No, ma'am. 8 Q. Did anybody ever tell you 9 that? 10 A. No. 11 Q. Are you aware at all that the 12 FDA was aware that Doctor Lu had done such a 13 study? 14 A. No. 15 Q. Have you ever seen a copy of 16 Doctor Lu's Fluoxetine-Maprotiline study? 17 A. I did ask him to send me a 18 copy, but I don't recall whether I received it or 19 not. 20 Q. Are you aware that there had 21 been studies prior to Doctor Lu's study that 22 indicated that a higher rate of suicidality was 23 associated with the use of Maprotiline? 24 A. That was what he mentioned Page 47 1 upon arrival when I picked him up from the 2 airport. 3 Q. Did he mention anything else 4 about the study on the way from the airport? 5 A. I told him I just don't -- not 6 knowledgable in that area to help him. 7 Q. Did he tell you that in his 8 study, seven out of sixty people on Fluoxetine 9 became suicidal while nobody on Maprotiline 10 became suicidal? 11 A. That detail, I'm not aware of. 12 Q. Have you ever been aware of 13 that? 14 A. No, I was not aware of that. 15 Q. Are you aware of that now? 16 A. Yes, now. 17 Q. When did you become aware of 18 that fact? 19 A. After his departure, yes. 20 Q. After his departure from 21 Lilly? 22 A. Yes. 23 Q. In February of 1992? 24 A. Yes. Page 48 1 Q. Did you attend any meeting 2 between Doctor Lu and any Lilly psychiatrist when 3 he was here in February of 1992? 4 A. On that occasion I did take 5 Doctor Lu to the meeting, and I sat down there, 6 and after they all introduced themselves and I 7 left. 8 Q. Did you ask to stay? 9 A. Did I ask to stay, no, I 10 didn't. 11 Q. Were you asked to leave? 12 A. I'm sorry? 13 Q. Were you asked to leave? 14 A. No. 15 Q. Why did you leave? 16 A. That was an area topic beyond 17 my area of interest, of knowledge. 18 Q. You helped in developing the 19 drug, correct? 20 A. Yes. 21 Q. How is it that you're not 22 interested in how the drug works or research on 23 how the drug works in humans then? 24 A. That is more than just a -- Page 49 1 there are many more published papers that 2 illustrate the efficacy of the drug. 3 Q. Have you ever had another 4 opportunity to talk with a doctor who has done a 5 study directly on using Fluoxetine on human 6 beings? 7 A. Yes. 8 Q. How many doctors? 9 A. At meetings, and I don't know -- 10 I mean it's difficult to count how many. 11 Q. Have you ever had the 12 opportunity to talk with doctors who have done 13 studies on Fluoxetine where it has -- where their 14 studies have shown adverse side effects or 15 adverse events, of any kind? 16 A. Would you -- 17 MR. MYERS: Has he ever talked to any -- 18 MS. ZETTLER: I'll ask it again. 19 Q. Have you ever had the 20 opportunity to talk to a doctor, such as Doctor 21 Lu, who has done a study on Fluoxetine, where it 22 indicates that there is -- patients have 23 experienced adverse events of any kind? 24 A. You are talking about Doctor Page 50 1 Lu or -- 2 Q. Any doctors. 3 A. Yes. 4 Q. Who? 5 A. Doctor Joe Wernicke. 6 Q. I'm talking about outside of 7 Lilly, let's talk outside of Lilly. 8 A. I don't recall having talked 9 to outside psychiatrists about side effect 10 profile. 11 Q. Wouldn't you be interested in 12 talking to somebody outside of Lilly who has done 13 a study who obviously doesn't have a bias in 14 favor of the drug? 15 MR. MYERS: Let me object to the form 16 since your question assumes that somebody would 17 have a bias in favor of the drug. 18 Q. Can you answer the question, 19 Doctor? 20 A. I have an interest to know 21 about the side effect profile, but there's enough 22 in the literature published and by reading in the 23 literature, and I get a fuller view about the 24 side effect profile, more complete. Page 51 1 Q. Yet you had an opportunity to 2 talk to a doctor who had actually conducted a 3 study related to a side effect profile of 4 Fluoxetine and you chose not to stay in the 5 meeting where he was discussing this? 6 A. I recall one time I did talk 7 to someone. 8 Q. Who? 9 A. And -- someone from Florida, 10 exactly the name of the doctor, I don't recall. 11 There was the combination of using Fluoxetine 12 with Trazodone or Benzodiazepine to help patient 13 to sleep. 14 Q. And it was a comparison of 15 Fluoxetine and Trazodone? 16 A. No, that's just his practice 17 experience. 18 Q. He used Trazodone in a 19 combination with Fluoxetine? 20 A. Beg your pardon? 21 Q. Did he use Trazodone in 22 combination with Fluoxetine? 23 A. Yes. 24 Q. And he used the Trazodone to Page 52 1 counteract some of the patient's inability to 2 sleep? 3 A. Because some had more sedative 4 effect. 5 Q. Trazodone doesn't have a 6 sedative effect? 7 A. Yes. 8 Q. When did you speak with this 9 doctor? 10 A. Three or four years ago. 11 Q. And who initiated that 12 conversation? 13 A. I did. 14 Q. Did you call the doctor? 15 A. No, it was a meeting. 16 Q. Where was the meeting? 17 A. One was a psychiatry meeting 18 and so the reason -- usually mostly the reason I 19 talked to psychiatrist is to learn from their 20 first-hand experience, like you assume that I 21 should, and I did and find out what mechanism 22 that would, that experience may lead to a new 23 understanding of antidepressive mechanism of 24 drug. So that was the reason for initiating the Page 53 1 conversation. 2 Q. Yet you had a chance to learn 3 from Doctor Lu's first-hand experience comparing 4 Fluoxetine and Maprotiline and you chose not to? 5 MR. MYERS: He answered that, Nancy, 6 you asked him that about three or four questions 7 ago. So I object, it's been asked and answered. 8 So answer the question again, Doctor Wong. 9 A. Which question? 10 MR. MYERS: She can read it back. 11 (THE COURT REPORTER READ BACK THE 12 REQUESTED TESTIMONY.) 13 A. Those were, as I recall those 14 were open studies and I don't recall exactly, 15 that's the reason why I didn't know exactly what 16 to ask, was this double blind study or not, so I 17 have no prior knowledge about the design of the 18 experiment and the value of the double-blind 19 experiment is so important and I appreciate data 20 generated from and the reason why a published 21 double-blind study, even though I have a much 22 interest in doctor's experience in treating 23 depression, but I will have to wait on the 24 design, the kind of design or experiment study Page 54 1 being done before I can take in knowledge 2 indiscriminately. 3 Q. So you weren't interested in 4 Doctor Lu's study because it was not a blinded 5 study? 6 A. To this day, I don't know if 7 it was blinded or not blinded. 8 Q. Did you ever ask him, Doctor? 9 A. I didn't ask. 10 Q. Why not? 11 A. That did not occur to me to 12 ask the question. I believe that at the time 13 that he was still -- from the conversation, it 14 seemed like he still had a lot of question 15 himself about his own work and for me to ask him 16 further doesn't seem to be productive didn't seem 17 to be productive at that time . 18 Q. What conversation are you 19 referring to where you say that he indicated he 20 had a lot of questions himself? 21 A. Well, that is the purpose of 22 his meeting, then I realize that upon picking him 23 up from the airport, that he needed to talk to 24 people. Page 55 1 Q. I'm having a little trouble 2 here, Doctor. First, on the one hand you said 3 you didn't discuss the study with Doctor Lu, 4 correct? 5 A. Yes. 6 Q. Then how did you have a 7 conversation with him where he indicated to you 8 that he still had questions about the study 9 himself? 10 A. Well, he wanted to seek advice 11 of psychiatrist, other psychiatrists, and that is 12 the extent of my understanding of his difficulty. 13 Q. But it's your earlier 14 testimony that he originally came to Indianapolis 15 to talk to Doctor Lumeng, right? 16 A. Uh-huh. That's why I was 17 surprised, yes, I was unprepared at the time. 18 Q. And the meeting that was 19 arranged with Doctor Lu and the Lilly 20 psychiatrist about his Maprotiline study was 21 arranged at Lilly's request, was it not? 22 A. I don't know. 23 (PLAINTIFFS' EXHIBIT NO. 3 WAS 24 MARKED FOR IDENTIFICATION AND Page 56 1 RECEIVED IN EVIDENCE.) 2 A. Yes, this is before his 3 arrival. 4 Q. Is this letter -- it's 5 addressed to David T. Wang, Ph.D. Is that a typo, 6 Doctor? 7 A. Yes, I think so. 8 Q. So this letter was addressed 9 to you, correct? 10 A. Right. 11 Q. And this letter was before his 12 arrival in the week of February 20, 1992, 13 correct? 14 A. Yes. 15 Q. And you testified earlier that 16 you didn't become aware of Doctor Wang's suicide 17 study or his meeting with the psychiatrists at 18 Lilly regarding that study until after he had 19 already arrived in Indianapolis, correct? I'm 20 asking you if that was your earlier testimony. 21 MR. MYERS: He's reviewing the 22 document. 23 A. I didn't understand the nature 24 of this conference. Yes, I'm aware that they Page 57 1 have -- this conference that he attempt to meet, 2 to have to arrange -- 3 Q. What was it you didn't 4 understand about a conference on Fluoxetine -- 5 A. Well -- 6 Q. Let me finish my question. 7 What is it that you don't understand about a 8 conference on Fluoxetine treatment and suicidal 9 attempts? 10 A. Well, I don't know what a 11 suicidal attempt that he's trying to -- the 12 nature of the conference, I don't understand. 13 That is only the topic that will be the 14 conference for. 15 Q. Doctor Wong, you just 16 testified a few minutes ago that the reason 17 Doctor Lu was originally asked or originally 18 brought to Indianapolis was to meet with Doctor 19 Lumeng about the alcoholic rats, right? 20 A. No, alcoholism. 21 Q. Alcoholism and his rats, 22 correct? 23 A. No, alcoholism. Because 24 Doctor Lumeng -- Doctor Lu is not -- doesn't use Page 58 1 the rat, but Doctor Lumeng have the interest in 2 using a rat as a model on alcoholism. 3 Q. So your testimony earlier was 4 that Doctor Lu came to Indianapolis to meet with 5 Doctor Lumeng about alcoholism, right? 6 A. Yes. 7 Q. Okay. And that you didn't 8 become aware of any meeting being set up between 9 Lilly employees and Doctor Lu regarding a 10 suicidal study on Fluoxetine until after he was 11 already here, did you not? 12 MR. MYERS: Object to the form, that's 13 not what he said. Go ahead and answer the 14 question. 15 A. It's not that I did not aware, 16 but I did not aware the nature of what -- being a 17 basic scientist, and when those topic come and 18 this is not my own area of activity, my 19 responsibility, so I didn't go into detail what 20 is going to be conferenced about except 21 Fluoxetine about suicidal attempt, that's the 22 only topic I aware of at the time. 23 Q. You received awards related to 24 your research on Fluoxetine, have you not? Page 59 1 A. Yes. 2 Q. And in fact that was a pivotal 3 project in your career, was it not? 4 A. Yes. 5 Q. And in a sense Fluoxetine is 6 your baby, is it not? 7 A. Yes. 8 Q. So why is it that you wouldn't 9 be interested or try to find out what the subject 10 was with Fluoxetine treatment and suicidal 11 ideation? 12 MR. MYERS: I object to the form, he 13 didn't say he wasn't interested, you 14 mischaracterized his testimony. 15 Q. What he said was that you 16 don't have any knowledge of it because that's not 17 your area, correct? 18 MR. MYERS: I object to the form, 19 that's not what he said either, he didn't say he 20 did not have any knowledge of it. 21 Q. Let me ask another question. 22 I'm trying to figure out why it is that a little 23 while ago you testified that it was your 24 understanding that Doctor Lu originally came to Page 60 1 Indianapolis to meet with Doctor Lumeng, and that 2 you didn't know that he was to meet with doctors 3 at Lilly regarding the Fluoxetine-Maprotiline 4 study until after he had already arrived here, 5 and now we have an exhibit that says otherwise. 6 A. Maybe I was -- I just gave you 7 my first-hand impression at the time upon his 8 arrival, and maybe my oversight not to read the 9 memo carefully. And, so, I also -- it was also 10 that I didn't pursue what is behind those -- that 11 arrangement of conference on Fluoxetine and 12 attempt suicide, and I admit that I have not 13 spent time in investigating the purpose of that 14 meeting. But that is the extent of my knowledge 15 of what I'm telling you. 16 MR. SMITH: I object to the answer as 17 being nonresponsive other than that comment that 18 said it was an oversight on his part. 19 Q. Who asked you to write to 20 Doctor Lu and invite him to meet with Lilly 21 psychiatrists regarding suicide and Fluoxetine? 22 A. Who asked me? 23 Q. Yes. 24 A. Perhaps Mister Lin, must be Page 61 1 Mister Lin. 2 Q. Why do you say that? 3 A. Nobody else have contacted me 4 about Doctor Lu's coming. 5 Q. Have you talked to Doctor 6 Zerbe about Doctor Lu's study? 7 A. No. 8 Q. Did you draft a letter to 9 Doctor Lu inviting him to meet with Lilly 10 psychiatrists regarding his study? 11 A. Did I draft a letter to invite 12 Doctor Lu, I invite Doctor Lu to come, is that 13 what you're asking? 14 Q. Exhibit Number 3 indicates 15 that you invited Doctor Lu to come to 16 Indianapolis to meet with Lilly personnel 17 regarding Fluoxetine and suicidal attempts, 18 correct? 19 MR. MYERS: I object to the form. The 20 letter speaks for itself, he didn't write it. Is 21 the question did you write a letter -- she wants 22 to know if you wrote a letter inviting him. 23 A. No , I didn't invite him. 24 Q. Did you talk to him on the Page 62 1 phone? 2 A. No. 3 Q. Did you convey an invitation 4 to Doctor Lu in any way? 5 A. No. 6 Q. Why did he write you this 7 letter saying thank you and Doctor Lumeng for 8 your invitation? 9 A. He's the one inititiated, he's 10 the one initiated it. 11 MR. SMITH: Doctor Wong, you're going 12 to need to let her finish the question before you 13 give your answer. And Ms. Zettler, you're going 14 to need to let him finish his responses before 15 you begin your question. Your objections are 16 overruled, by the way, Counselor. 17 MR. MYERS: Thank you, Mister Smith. 18 Q. So now you're saying that 19 Doctor Lu initiated the request for the meeting 20 in Indianapolis regarding suicide attempts and 21 Fluoxetine treatment? 22 MR. MYERS: I object to the form, 23 Nancy, you mischaracterized the testimony. He 24 told you about twenty minutes ago that Doctor Lu Page 63 1 called him about Doctor Lumeng, that was the 2 contact. 3 MS. ZETTLER: He also said twenty 4 minutes ago that he didn't realize or didn't know 5 of the meeting about suicidal ideation until he 6 got here in Indianapolis, Larry, and you know it. 7 MR. MYERS: That's not what he said. 8 MS. ZETTLER: I have a right to ask 9 him these question. 10 MR. MYERS: You have a right to ask a 11 proper question, and I'm telling you you 12 mischaracterized his testimony. The only thing 13 that's clear is that Doctor Lu calling him about 14 Doctor Lumeng. 15 MR. SMITH: Larry, we object to your 16 sidebar comments. This is cross-examination, she 17 has a right to question a memory that's already 18 been demonstrated to be faulty or evasive. 19 MR. MYERS: Well, Mister Smith, I will 20 object as I see fit. 21 MR. SMITH: We object to your sidebar 22 comments and interrupting these procedures. 23 MR. MYERS: That's fine, your 24 objection is noted. Page 64 1 MS. ZETTLER: And you're instructing 2 the witness through your objection. 3 MR. SMITH: We may get that ruling. 4 MR. MYERS: That's fine, judges rule 5 on objections. Go ahead and ask him another 6 question or the same question or have it read 7 back. 8 Q. (BY MS. ZETTLER) Doctor, did 9 you or did you not invite Doctor Lu to meet with 10 personnel at Eli Lilly regarding his study on 11 Fluoxetine treatment and suicidal attempts? 12 A. I only recall that it was his 13 request to be invited to come to Indianapolis, 14 and it's not me to initiate the invitation. 15 Q. He contacted you and asked to 16 be invited to Indianapolis to meet with Doctor 17 Lumeng, correct? 18 A. And to visit Lilly, I suppose, 19 yes, based on this letter. 20 Q. You remember that specifically 21 or are you guessing now? 22 A. This is the best of my 23 recollection, ma'am. 24 Q. What is the best of your Page 65 1 recollection? 2 A. That I was asked that Doctor 3 Lumeng -- I was asked that Doctor Lu like to 4 visit Indianapolis, visit Lilly, and asked me to 5 extend invitation to him. 6 Q. To visit Lilly? 7 A. To visit. 8 Q. Not to visit Doctor Lumeng? 9 A. To visit Doctor Lumeng and 10 Lilly as well. 11 Q. What is it that refreshes your 12 recollection as to that fact? 13 A. That's what I intended before, 14 as well, my -- maybe I didn't get it as clear as 15 I have in repeat exercising of my statement. 16 Q. So now it is your recollection 17 that Doctor Lumeng called you, contacted you -- 18 A. No, Doctor Lu. 19 Q. I'm sorry, Doctor Lu contacted 20 you and asked to be invited to Indianapolis to 21 meet with Doctor Lumeng and to visit Lilly? 22 A. Yes. 23 Q. Is it your recollection that 24 Doctor Lu asked to visit Lilly regarding his Page 66 1 suicide Fluoxetine study? 2 A. That is the only time that I 3 come across. If that is any occasion about 4 suicidal event, that is the only time that it had 5 occurred, because I didn't realize about the 6 background behind his interest in coming to 7 Indianapolis. 8 Q. That wasn't my question. My 9 question is, do you recall Doctor Lumeng asking 10 you to set up an invitation -- I'm sorry, Doctor 11 Lu setting up an invitation to visit Lilly to 12 discuss his Fluoxetine suicide study? 13 A. To the best of my knowledge, I 14 have no knowledge about this suicidal aspect of 15 his interest in coming. 16 Q. Did he say that he wanted to 17 come to Lilly to discuss his 18 Fluoxetine-Maprotiline study? 19 A. To that even, I don't recall 20 that even mentioned, I didn't even recollect he 21 was requesting to discuss about Fluoxetine and 22 Maprotiline. 23 Q. At some point you did become 24 aware of that, did you not, because you did Page 67 1 secure an invitation to Lilly for him, correct? 2 MR. MYERS: I think what she wants to 3 know, Doctor, is did you secure an invitation for 4 this doctor to visit Lilly. 5 MS. ZETTLER: That's not my question. 6 You can read the question back, Kathy. 7 (THE COURT REPORTER READ BACK THE 8 REQUESTED TESTIMONY.) 9 A. Again, I don't remember 10 whether I was the one who arranged the meeting 11 with the psychiatrists or Lilly Taiwan arranged 12 for him. 13 Q. Exhibit Number 3 indicates 14 that you were the one who invited him to Lilly, 15 does it not? 16 A. I more or less just a person 17 of contact, and I don't remember how much on my 18 part to initiate arrangement of the meeting. 19 Q. Doctor Lumeng would not have 20 invited Doctor Lu to come to Lilly, right? 21 A. Right, that part I did make 22 the contact for him to talk to Doctor Lumeng, 23 yes, I did arrange that. 24 Q. That's not my question. Page 68 1 Please listen to my questions, and I know I talk 2 fast so if I'm going too fast, let me know and 3 I'll slow down and rephrase it, whatever you 4 want, but please listen to my question, okay? 5 A. Yes. 6 Q. My question is: Doctor Lumeng 7 would not have been the person -- 8 A. Doctor Lu. 9 Q. Doctor Lumeng would not have 10 been the person to invite Doctor Lu to come to 11 Eli Lilly to discuss Doctor Lu's study, correct? 12 A. Doctor Lumeng invitation was 13 for him to come to discuss alcoholism with Doctor 14 Lumeng. 15 Q. Right. Doctor Lumeng would 16 not have had anything to do with inviting Doctor 17 Lu to Eli Lilly because he isn't affiliated with 18 Eli Lilly, right? 19 A. Correct. 20 Q. Okay. You were the person who 21 initiated or arranged the invitation for Doctor 22 Lu to come to Lilly to discuss the study with 23 doctors at Lilly, right, you are the one that 24 called Doctor Lu or wrote to Doctor Lu and said Page 69 1 Doctor Lu, I've got your invitation to come to 2 visit Lilly. 3 MR. MYERS: I object to the form, 4 you've mischaracterized his testimony and that's 5 about the fifth different time you've asked him 6 that question, whether he did it or not. 7 MS. ZETTLER: He hasn't answered the 8 question, Larry, and you know it. 9 A. I didn't write invitation to 10 Doctor Lu. 11 Q. Did you contact Doctor Lu in 12 any way and indicate to him that he was in fact 13 invited to Eli Lilly to meet with doctors or 14 other personnel at Lilly to discuss his 15 Fluoxetine treatment study? 16 A. I did not, I did not 17 personally invite Doctor Lu to Lilly. 18 Q. Who did? 19 A. He himself invite himself to 20 come, he want to come. 21 Q. Doctor Lu's letter to you says 22 thank you and Doctor Lumeng very much for your 23 invitation, not for fulfilling my request for an 24 invitation, correct? Page 70 1 MR. MYERS: She wants to know if 2 that's what it says. 3 A. It says, yes. 4 Q. Now, your testimony has been 5 that Doctor Lu contacted you and asked for you to 6 arrange for a meeting between him and Doctor 7 Lumeng, correct? 8 A. Yes. 9 Q. And for an invitation to Lilly 10 to meet to discuss his study or for some reason 11 that you don't recall, correct, two different 12 invitations? 13 A. For him, I only arranged it so 14 he could come to Indianapolis to meet with Doctor 15 Lumeng, and he also have contact with Lilly 16 Taiwan to make arrangement as well. So my part 17 is mainly for him to come to Indianapolis to meet 18 with Doctor Lumeng. 19 Q. Did you make travel 20 arrangements or accommodation arrangements? 21 A. No. 22 Q. Was Doctor Lumeng at the 23 dinner at your house? 24 A. No. Page 71 1 Q. Was Doctor Lumeng involved at 2 all with any meetings between Doctor Lu and Lilly 3 personnel when he was here in Indianapolis in 4 February of 1992? 5 A. Would you repeat, please? 6 Q. Was Doctor Lumeng involved in 7 any of the meetings between Lilly personnel and 8 Doctor Lu when Doctor Lu was here in February of 9 1992? 10 A. No. 11 Q. Are you saying that Doctor Lu 12 was confused when he wrote to you and thanked you 13 for your invitation to have a conference on 14 Fluoxetine treatment and suicide attempts in 15 February of 1992? 16 MR. MYERS: I object to the form. 17 Whether the fellow was confused when he wrote the 18 letter would be speculative for him to know that. 19 You can answer it, if you know. 20 A. I don't know whether he was 21 confused or not confused. 22 Q. He asked you later on in that 23 exhibit to arrange the meeting at Lilly for -- 24 MR. MYERS: Which one? Page 72 1 MS. ZETTLER: Exhibit 3. 2 MR. MYERS: Exhibit 3. 3 Q. In that exhibit he asked that 4 you try to arrange for the meeting on February 5 26th or 27th, is that correct? 6 A. Yes. 7 Q. Why would Doctor Lu be writing 8 to you thanking you for an invitation that you 9 didn't make? 10 MR. MYERS: I object to the form, 11 again, that would be speculation as to why Doctor 12 Lu wrote anything. 13 A. He know that I'm working in 14 Lilly and asked me to arrange for him to have a 15 delay of his visit, and that is not unusual about 16 it, I don't know why. 17 Q. Do you know if Lilly paid for 18 Doctor Lu's air fare to Indianapolis. 19 A. I have no knowledge. 20 Q. Do you know if they paid for 21 his accommodations here in Indianapolis? 22 A. At most, would be the hotel. 23 Q. Do you know what hotel he 24 stayed at while he was here? Page 73 1 A. That occasion, I took him to 2 the hotel at airport. 3 Q. You picked him up from the 4 airport and took him to the hotel at the airport? 5 A. Yes, the Adams Mark. 6 MR. MYERS: Adams Mark. 7 Q. Adams Mark. 8 MS. ZETTLER: Let's take a break. 9 (A SHORT RECESS WAS TAKEN.) 10 Q. (BY MS. ZETTLER) Doctor Wong, 11 once Doctor Lu contacted you and asked you to 12 arrange an invitation to Eli Lilly, what did you 13 do? 14 A. Wait for his coming, I mean -- 15 Q. Did you talk to anybody at 16 Lilly to arrange for a meeting between Doctor Lu 17 and Lilly psychiatrists? 18 A. I notified them. 19 Q. Who did you notify? 20 A. I'm sorry? 21 Q. Who did you notify? 22 A. I believe Doctor Beasley. 23 Q. Anybody else? 24 A. And Doctor Garry Tollefson, I Page 74 1 believe. 2 Q. How about Allen Weinstein? 3 A. I don't recall any contact 4 with Doctor Weinstein. 5 Q. What did you tell Doctor 6 Beasley and Doctor Tollefson about your 7 conversation with Doctor Lu? 8 A. Mainly for them to meet. 9 Q. Were Doctor Beasley and Doctor 10 Tollefson interested in meeting with Doctor Lu? 11 A. I have not received any 12 reaction of that nature. 13 Q. What did they say when you 14 told them that Doctor Lu wanted to meet with 15 them? 16 A. The meeting was scheduled, 17 their meeting arranged. 18 Q. Who arranged the meeting? 19 A. Since I was the person being 20 contacted, that most likely would be myself. 21 Q. Do you recall arranging the 22 meeting? 23 A. I only mention of his coming 24 because the detail of the meeting, I was not Page 75 1 involved in arranging. 2 Q. When you say the details of 3 the meeting, what do you mean? 4 A. Like time, location, meeting 5 rooms, that kind. 6 Q. How about dates? 7 A. Beg your pardon? 8 Q. How about the dates? 9 A. The dates of his arrival, yes. 10 Q. Yes? 11 A. Yes. 12 Q. Have you worked with Doctor 13 Lumeng on any rat studies related to serotonin 14 reuptake inhibitors? 15 A. Me? 16 MR. MYERS: Yes. 17 A. Yes. 18 Q. What studies? 19 MR. MYERS: Wait a second. If they 20 have to do with Fluoxetine, you can tell her 21 about them, if they have to do with a compound 22 that's not marketed, you can give her a general 23 description, you don't have to disclose any 24 compound other than Fluoxetine. Page 76 1 Q. Did you work with Doctor 2 Lumeng on studies regarding Fluoxetine? 3 A. Doctor Lumeng did study 4 Fluoxetine, but not with me. He only requested 5 Fluoxetine like everybody else requested 6 Fluoxetine for a study, but Doctor Lumeng and I 7 have collaboration on alcohol-preferring rats. 8 Q. Okay. Were the alcohol rat 9 studies related to Fluoxetine? 10 A. No -- are you referring to the 11 study that we did together? 12 Q. Right. 13 A. No. 14 Q. Did it relate to other 15 serotonin reuptake inhibitors, without being 16 specific? 17 A. Yes. 18 Q. Okay. Was your collaboration 19 with Doctor Lumeng before or after Doctor Lu's 20 visit to Indianapolis in February of 1992? 21 A. Before. 22 Q. How long had you known Doctor 23 Lumeng prior to Doctor Lu's visit to Indianapolis 24 in February of 1992? Page 77 1 A. We know of each other for some 2 time as casual friends because there aren't too 3 many Chinese in town. 4 Q. Do you recall when you first 5 met Doctor Lumeng? 6 A. In some of the community 7 functions. 8 Q. But how long before Doctor 9 Lu's visit to Indianapolis in February of 1992? 10 A. Oh, in the '70's. 11 Q. If you could look at Exhibit 12 Number 1 again, please, Doctor. 13 A. Yes. 14 Q. Towards the bottom of the page 15 before you sign off, it says this serves as my 16 brief report. Do you see that? 17 A. Yes. 18 Q. Did you write a longer report 19 about your meeting with Doctor Lu? 20 A. No. 21 Q. At the bottom you say PS, 22 clarification to emphasize that they'll reanalyze 23 their data by following Doctor Beasley's 24 published methods. Do you see that? Page 78 1 A. Yes. 2 Q. Do you recall when they told 3 you that? 4 A. Before -- when I took them 5 back to the hotel, that's what he said. 6 Q. The night they had dinner at 7 your house? 8 A. Yes, after dinner at the 9 house. 10 Q. When you took them back to the 11 hotel? 12 A. Yes, when they said good-bye, 13 that's what they said. 14 Q. Doctor Beasley was not at 15 dinner? 16 A. No. 17 Q. Any other employees from Eli 18 Lilly at the dinner? 19 A. No, just my wife and myself. 20 Q. And the two doctors from 21 Taiwan? 22 A. Yes. 23 Q. So when Doctor Lu told you 24 that they would reanalyze the data by following Page 79 1 Doctor Beasley's published methods, how did that 2 come up? 3 A. Repeat again. 4 Q. Sure. How did Doctor Lu's 5 comment about reanalyzing the data from his study 6 using Doctor Beasley's method come up? 7 A. I asked how was the meeting 8 went, and they said we'll reanalyze the data, 9 that was all I gathered. 10 Q. Did you as them -- did you try 11 to get more information out of them about the 12 meeting? 13 A. Well, I didn't try to, I just 14 say how was today. 15 Q. Did somebody at Lilly ask you 16 to try to get Doctor Lu's opinion of the meeting 17 out of him? 18 A. No. 19 Q. Did somebody at Lilly ask you 20 to try to sway Doctor Lu to not publish his 21 Maprotiline study? 22 A. No. 23 Q. So it's your testimony that 24 you were not involved in a concerted effort by Page 80 1 Eli Lilly to prevent Doctor Lu from publishing 2 his Maprotiline study? 3 MR. MYERS: Before he answers, let me 4 object to the form to the extent you assume that 5 there was such an effort. 6 A. I was not aware. 7 MR. MYERS: You can answer the 8 question. 9 A. I'm not aware of such attempt. 10 Q. So your testimony is that you 11 were not a part of that attempt? 12 MR. MYERS: I object to the form again 13 on the same basis. He said he wasn't aware of 14 it. 15 Q. Were you involved in a mission 16 at Eli Lilly to secure Doctor Lu's nonpublishing 17 of his report? 18 MR. MYERS: Same objection. 19 A. I didn't quite hear. 20 Q. Were you involved in a mission -- 21 A. Omission? 22 Q. Mission, M-I-S-S-I-O-N -- 23 A. Oh. 24 Q. -- At Lilly to prevent Doctor Page 81 1 Lu from publishing his Maprotiline study? 2 A. No. 3 Q. Were you aware that such a 4 mission was being undertaken at Lilly? 5 MR. MYERS: Same objection as to form. 6 Answer. 7 MR. HARRIS: Also, it requires the 8 witness to speculate. 9 A. I'm not aware of such a 10 mission. 11 (PLAINTIFFS' EXHIBIT NUMBER 4 12 WAS MARKED FOR IDENTIFICATION AND 13 RECEIVED IN EVIDENCE.) 14 Q. Have you read Exhibit Number 15 4? 16 A. Yes, I read it. 17 Q. Have you ever seen this 18 exhibit before, Doctor? 19 A. No. 20 Q. The exhibit purports to be an 21 E-Mail dated April 8, 1992 written by Allen 22 Weinstein, correct? 23 A. Yes. 24 Q. And the E-mail states,"Mission Page 82 1 successful. Professor Lu will not present or 2 publish his Fluoxetine versus Maprotiline 3 suicidality data," does it not? 4 MR. MYERS: I object to the form only 5 because that's not what it says in its entirety, 6 that's what it says in part, I think, if you read 7 it right. 8 Q. The first sentence of that 9 E-Mail says mission successful, does it not? 10 A. It does. 11 Q. That implies that there was a 12 mission, does it not? 13 MR. MYERS: I object to the form, he's 14 already answered that question. 15 MS. ZETTLER: I don't think he has. 16 A. What was the question again, 17 please? 18 Q. The sentence mission 19 successful implies that there was a mission that 20 succeeded, does it not? 21 MR. MYERS: Same objection, and it 22 would also call for him to speculate since he 23 didn't write it. 24 MS. ZETTLER: I think he can read Page 83 1 English. 2 Q. Can't you, Doctor? 3 MR. MYERS: Is that the question, 4 whether he can read English or not? 5 Q. Yes, you can read English, 6 can't you, Doctor? 7 MR. MYERS: She wants to know if you 8 can read English, that's all she wants to know. 9 A. I don't know what the author 10 meant by mission. 11 Q. That's not my question. Can 12 you or can you not read English? 13 A. I can. 14 Q. And the first sentence of that 15 E-Mail says mission successful, does it not? 16 A. It does. 17 Q. And implies that there was a 18 mission that succeeded, does it not? 19 MR. MYERS: Same objection as to form, 20 it calls for him to speculate. 21 Q. You can answer the question. 22 A. I cannot assume there was a 23 mission. 24 Q. All I'm asking about is that Page 84 1 one simple sentence, Doctor. 2 MR. MYERS: He's already answered 3 that. Don't answer that question again, Doctor 4 Wong. Ask him another question, Nancy. 5 Q. Questions like this get Larry 6 upset. Second line of the E-Mail says Professor 7 Lu will not present or publish his Fluoxetine 8 versus Maprotiline suicidality data, does it not? 9 MR. MYERS: The second sentence says 10 that. 11 MS. ZETTLER: That's what I meant. 12 A. It does. 13 MR. SMITH: Why don't you be quiet. 14 MR. MYERS: No, she wants to know -- 15 MS. ZETTLER: He's answered it. He 16 said yes, I believe. 17 Q. Doctor, did you say yes? 18 A. It says. 19 Q. Were you aware that there was 20 a mission at Eli Lilly to prevent Doctor Lu from 21 publishing his Fluoxetine versus Maprotiline 22 suicidality data? 23 MR. MYERS: I object to the form in 24 that you assume that there was such a mission. Page 85 1 He answered that four or five questions ago. 2 MS. ZETTLER: I was asking about the 3 study, and now I'm asking about the suicidality 4 data. 5 A. I am not aware of such a 6 mission. 7 Q. Who is Michael Chen? 8 MR. MYERS: He's not on this document, 9 is he? 10 MS. ZETTLER: Right. 11 A. Michael Chen. How do you 12 spell the last name? 13 Q. C-H-E-N. 14 A. Do I know -- do I supposed to 15 know this person? 16 MR. MYERS: She just wants to know if 17 you know who he is, that's all she wants to know. 18 Q. Do you know Mister Chen, 19 Michael Chen? 20 A. I don't. 21 Q. Okay. Are you aware that 22 Lilly offered to work with Doctor Lu to do 23 another study comparing Fluoxetine versus 24 Maprotiline? Page 86 1 A. No, I don't. 2 Q. Have you been in contact with 3 Doctor Lu since February of 1992? 4 A. Last year one evening he 5 called me at home, and that's the only occasion 6 that I have contact with him. 7 Q. Why did he call you at home? 8 A. He asked for telephone number. 9 Q. Whose telephone number? 10 A. Doctor Weinstein's telephone 11 number. 12 Q. Did you give it to him? 13 A. I have no -- I don't have 14 Doctor Weinstein's telephone number. 15 Q. What did you tell him? 16 A. That's what I told him. 17 Q. Is Doctor Weinstein still with 18 Lilly? 19 A. As far as I know, he is. 20 Q. Did you tell him to call him 21 at Lilly headquarters? 22 A. Yes, I -- probably that's what 23 I did. 24 Q. Did he say why he wanted Page 87 1 Doctor Weinstein's phone number? 2 A. He hang up phone before I have 3 a chance to ask him. 4 Q. How was his demeanor on the 5 phone? 6 A. I'm sorry? 7 Q. How was his demeanor on the 8 phone, was he angry? 9 MR. MYERS: Let me object to the form, 10 you're asking him to speculate as to what the 11 fellow at the other end of the telephone was -- 12 MS. ZETTLER: I'm asking for his 13 impression, Larry, and you know it. 14 A. No, he was very pleasant. 15 Q. Any other conversation besides 16 him saying Hi, Doctor Wong, this is Doctor Lu, 17 give me Allan Weinstein's phone number? 18 A. Yes. 19 Q. What else? 20 A. That's about it. 21 Q. There was nothing else he 22 said? 23 A. We always say how are you, and 24 that's about it. Page 88 1 Q. Did you ask him what was new 2 or what he was working on or anything like that? 3 A. No. 4 Q. Did he say anything to you 5 about what he was working on? 6 A. No, except that he was turned 7 out to be in either Boston or somewhere in 8 Massachusetts. 9 Q. Was he at Yale? 10 A. Beg your pardon? 11 Q. Was he at Yale? 12 A. I don't recall. 13 Q. Do you know what he was doing 14 in Boston or Massachusetts? 15 A. I believe that he did mention 16 will be there for sabbatical. 17 Q. When was this conversation? 18 A. Beg your pardon? 19 Q. When did you have this 20 telephone conversation? 21 A. The evening. 22 Q. What year? 23 A. Last year. 24 Q. Did he say how long he was Page 89 1 going to be here on sabbatical? 2 A. That, I didn't ask how long he 3 would be there. 4 Q. Were you aware that Doctor Lu 5 was in the country until about August of 1993? 6 A. Uh-uh, no. 7 Q. Other than that conversation 8 on the phone with Doctor Lu, have you spoken with 9 him since the February, 1992 meeting at Lilly? 10 A. No, ma'am. 11 Q. Did you contact Doctor Lu in 12 any way? 13 A. I'm sorry? 14 Q. Since February of 1992, did 15 you contact Doctor Lu in any way? 16 A. I didn't initiate any contact. 17 Q. Did he contact you in any way 18 after the 1992 meeting other than this phone 19 call? 20 A. That's the only. 21 Q. Did you tell Doctor Weinstein 22 that Doctor Lu was looking for him? 23 A. No. 24 Q. Did Doctor Weinstein ever Page 90 1 mention to you that Doctor Lu had gotten in touch 2 with him? 3 A. No. 4 Q. Who is Doctor Weinstein? 5 A. He's a medical doctor. 6 Q. Do you know what his 7 responsibilities are with regards to Fluoxetine? 8 A. I don't know. 9 Q. Do you know what his 10 responsibilities with regards to Fluoxetine in 11 early 1992 were? 12 A. I don't know. 13 Q. Is he a medical monitor on 14 Fluoxetine? 15 A. That, I know he wasn't a 16 medical monitor. 17 Q. Was he a research physician as 18 far as you know? 19 A. In the medical division. 20 Q. Do you know if he was a 21 research physician on Fluoxetine? 22 A. I don't believe so. 23 Q. Is he a vice-president? 24 A. Yes, I believe. Page 91 1 Q. When did he become 2 vice-president? 3 A. Several years back, I don't 4 recall exact date. 5 Q. Before Doctor Lu came to Lilly 6 in 1992? 7 A. Relatively speaking, I believe 8 so. 9 Q. When you say relatively 10 speaking, what do you mean? 11 A. Because I don't recall exact 12 date when Doctor Weinstein become vice-president. 13 Q. But it's your belief that it 14 was before Doctor Lu came to -- 15 A. Yes, I believe so. 16 Q. Let me finish my question so 17 Paul doesn't yell at us again, okay? 18 A. Okay. 19 Q. Have you ever heard of a 20 Robert Luedke, L-U-E-D-K-E? 21 A. No. 22 Q. Have you heard of Christopher 23 Shaw? 24 A. Yes. Page 92 1 Q. Who is Christopher Shaw? 2 A. Currently he's in Lilly 3 Taiwan, he's an Englishman. 4 Q. What is his position with 5 Lilly in Taiwan? 6 A. He's a managing director. 7 Q. Has he ever worked here in 8 Indianapolis? 9 A. Beg your pardon? 10 Q. Has he ever worked in 11 Indianapolis at Lilly? 12 A. Yes. 13 Q. When? 14 A. Until somewhere between the 15 middle of last year. 16 Q. Okay. Was he here during the 17 early part of 1992? 18 A. Yes. 19 Q. Do you recall whether or not 20 he helped to arrange the meeting between Doctor 21 Lu and the Lilly personnel? 22 A. I don't recall. 23 Q. Who is George Grubb, 24 G-R-U-B-B, or Grubb? Page 93 1 A. I have seen that name before, 2 but I don't recall who it was. 3 (PLAINTIFFS' EXHIBIT NO. 5 WAS 4 MARKED FOR IDENTIFICATION AND 5 RECEIVED IN EVIDENCE.) 6 Q. Have you reviewed Exhibit 7 Number 5? 8 A. I did. 9 Q. And in that exhibit, it talks 10 about you coordinating the schedule with George 11 Grubb, correct? 12 A. Correct. 13 Q. The schedule for Doctor Lu's 14 visit to Indianapolis, his meeting? 15 A. As a contact person, yes. 16 Q. And the E-mail states that, I 17 guess it's Mister Grubb, or George Grubb is an 18 international plans associate? 19 A. Yes. 20 MR. MYERS: You said it was an E-mail, 21 I don't know if it is or isn't. It doesn't look 22 like one. I just don't know the answer to that. 23 Q. Okay. This document, the 24 communication, we'll call it. It says facsimili Page 94 1 at the top, correct, Doctor? 2 A. Yes. 3 Q. It's dated February 4th? 4 A. Yes. 5 Q. And it's written by 6 Christopher Shaw? 7 A. Yes. 8 Q. Other than this time where you 9 coordinated the schedule for Doctor Lu's visit 10 with George Grubb, have you spoken with Mister 11 Grubb? 12 A. I don't recall whether 13 speaking to him, when you talk about speaking, 14 but I must have made contact with him for this 15 occasion, for this event. 16 Q. Okay. Do you recall if you -- 17 how you communicated with George Grubb about 18 setting up a schedule? 19 A. To have record of my 20 communication, that would help me. 21 Q. No, I don't have one 22 unfortunately. 23 A. So I don't recall how I made 24 contact. Page 95 1 Q. What was Doctor Tollefson's 2 role in the meeting with Doctor Lu? 3 A. I only aware that he is a 4 psychiatrist, and I don't know exactly what role 5 that he played. 6 Q. How about Allen Weinstein's 7 role in the meeting with Doctor Lu, if any? 8 A. I don't know whether there was 9 a meeting of Doctor Weinstein and Doctor Lu. 10 Q. Did you talk with Doctor 11 Weinstein at all about Doctor Lu's coming to 12 Indianapolis or his study? 13 A. No. 14 Q. Were you surprised that Doctor 15 Weinstein was involved in this at all? 16 A. Since he's in medical area, I 17 have no -- I don't have a feeling one way or the 18 other whether I'm surprised or not surprised. 19 Q. Were you told prior to Doctor 20 Lu's arrival in Indianapolis who he would be 21 meeting with at Lilly regarding the study? 22 A. Could you repeat again? 23 Q. Were you told prior to Doctor 24 Lu's arrival in Indianapolis who he would be Page 96 1 meeting with at Lilly regarding the study? 2 A. I mentioned only my 3 recollection was Doctor Beasley and Doctor 4 Tollefson. 5 Q. Did you know that before 6 Doctor Lu actually got here? 7 A. Because I asked for their 8 availability. 9 Q. So the answer is yes, you knew 10 that before he got here. 11 A. Yes, uh-huh. 12 Q. Do you know of anybody else 13 from Lilly who contacted Doctor Lu besides 14 yourself and Dennis Lin regarding this meeting? 15 A. I don't remember anybody else. 16 Q. Have you personally had 17 contact with anybody at the FDA regarding 18 Fluoxetine? 19 A. Personally means that -- 20 Q. Conversations, meetings, 21 letters, any contact. 22 A. No. 23 Q. Have you attended any meetings 24 at the FDA? Page 97 1 A. Yes, I did. 2 Q. When was the first meeting 3 that you attended -- and I want to know 4 specifically about Fluoxetine, meetings about 5 Fluoxetine. 6 A. I understand. 7 Q. When was the first meeting 8 that you attended with the FDA about Fluoxetine? 9 A. The first time was with the 10 Fluoxetine project team members to visit the FDA 11 about the observation that in -- I believe it was 12 in dog studies that there was accumulation of 13 phospholipidosis. 14 MR. HARRIS: I'm sorry, what studies? 15 THE WITNESS: Phospholipidosis. 16 Q. What is phospholipidosis? 17 A. In the tissue, it may 18 accumulate lipid. 19 Q. What tissue? 20 A. The lung. 21 Q. Why were you involved in that 22 meeting? 23 A. Because I was a member of the 24 project team. Page 98 1 Q. Were you aware of the dog 2 studies? 3 A. I beg your pardon? 4 Q. Were you aware of the dog 5 studies before the FDA meeting? 6 A. Yes, that's why we approached 7 the FDA. 8 Q. You approached the FDA, the 9 team approached? 10 A. I didn't, the team approached 11 the FDA. 12 Q. What did the dog studies show 13 about phospholipidosis? 14 A. In that experimental animal, 15 that Fluoxetine have in the animal treated with 16 Fluoxetine, have appearance of phospholipidosis 17 in the lung tissue. 18 Q. Were those studies conducted 19 by Lilly? 20 A. In toxicology study, yes. 21 Q. That's Lilly toxicology 22 studies? 23 A. Yes. 24 Q. So to make sure I understand Page 99 1 this, the dog studies showed that at least dogs 2 that were exposed to Fluoxetine began suffering 3 from phospholipidosis, correct? 4 A. Began showing 5 phospholipidosis. 6 Q. They weren't suffering. 7 A. That's right. 8 Q. When did that meeting take 9 place? 10 A. When? 11 Q. When. 12 A. That was before the Phase 1 13 trial. 14 Q. Can you give me a year? 15 A. Maybe '74, '75. 16 Q. And what was the result of 17 that meeting? 18 A. To know that there are many -- 19 we were informed that many current and marketed 20 medications have similar findings in experimental 21 animals. 22 Q. When you say other currently 23 marketed medications, are you talking about 24 specifically antidepressants? Page 100 1 A. Antihistamine. 2 Q. Other drugs generally? 3 A. Yes, uh-huh. 4 Q. Did anybody at Lilly 5 extrapolate from the phospholipidosis dog studies 6 at Lilly as to what effect that may have on 7 humans? 8 A. That's the reason why need to 9 consult with the FDA. 10 Q. There was nobody at Lilly that 11 could make that extrapolation? 12 A. The experience of 13 phospholipidosis is not as common in the person 14 that was working on the toxicology, on Fluoxetine 15 at the time, and so the FDA have broader 16 experience with other drugs' action, and that's 17 the reason why the FDA was consulted. 18 Q. My question was was there 19 anybody at Lilly that could extrapolate the 20 results of the dog studies showing 21 phospholipidosis to its effect on human beings? 22 A. That is the purpose of to 23 consult with the FDA, that must be that 24 extrapolation is still a concern, and that's the Page 101 1 reason why we approached the FDA. 2 Q. You still haven't answered my 3 question. 4 MR. MYERS: Here's what she wants to 5 know -- 6 MS. ZETTLER: Let me ask it, Larry. 7 MR. MYERS: Go ahead. 8 Q. Was there anybody at Eli Lilly 9 that could have extrapolated any impact on human 10 beings from what you found in the dog studies 11 where the dogs suffered from phospholipidosis? 12 MR. MYERS: Before they went to the 13 FDA? 14 Q. Before you went to the FDA. 15 A. No. 16 Q. What type of scientist or 17 doctor would be qualified to make that 18 extrapolation? 19 A. Perhaps a pulmonary physician 20 in a pulmonary disorder. 21 Q. Did you have any pulmonary 22 physicians on staff at Lilly or its clinics? 23 MR. MYERS: When? 24 MS. ZETTLER: Before he went to the Page 102 1 FDA with the dog phospholipidosis studies. 2 A. I don't know what -- I assume 3 there must be because that is the -- the 4 clinicians that would oversee the development of 5 antibiotics. 6 Q. Are you aware that there were 7 trials on normal humans at the Lilly clinic on 8 Fluoxetine? 9 A. I'm sorry? 10 Q. Were you aware that there were 11 trials performed on normal human beings at the 12 Lilly clinic on Fluoxetine? 13 MR. MYERS: At what point in time? 14 MS. ZETTLER: Probably late '70s, 15 early '80s. 16 A. The Phase 1 study was 17 conducted. 18 Q. Do you know if any 19 pulmonologists or cardiologists were working on 20 those studies? 21 A. To be specific, I don't 22 recall. But that -- the possibility of 23 phospholipidosis in human was a fact that we were 24 being watchful if that would occur. Page 103 1 Q. Were there any cardiologists 2 or pulmonologists on the project team, the 3 Fluoxetine project team that you were a member 4 of? 5 MR. MYERS: At any time while he was 6 on it? 7 MS. ZETTLER: Yes. 8 A. The project team consult with 9 cardiologists. 10 Q. But there was not a member of 11 the team, as far as you know, that was a 12 cardiologist or pulmonologist? 13 A. I don't recall such a 14 specialist being in the team. 15 Q. And the FDA assured you that 16 in other drugs that had been marketed, 17 phospholipidosis had occurred in test animals? 18 A. Yes. 19 Q. And that didn't necessarily 20 extrapolate into that occurring in human beings, 21 correct? 22 A. That was the impression that 23 we received, yes. 24 Q. Did they ask you to do any Page 104 1 further testing on Fluoxetine with regards to 2 phospholipidosis in human beings? 3 A. Whether they request or not, I 4 don't recall. 5 Q. Were any further tests done? 6 A. Since I'm not a toxicologist, 7 I'm not in charge of that aspect of it, but I do 8 know that the reversability of the effect of 9 Fluoxetine was investigated. 10 Q. The reversability? 11 A. Yes. 12 Q. Of the effect of Fluoxetine? 13 A. Yes. 14 Q. As it related to 15 phospholipidosis? 16 A. Yes. 17 Q. Were there studies that were 18 done that showed that some human beings did 19 suffer from phospholipidosis as a result of 20 ingestion of Fluoxetine? 21 A. No evidence had ever been 22 reported. 23 Q. That's not my question. Were 24 studies done, to your knowledge, that showed that Page 105 1 human beings exposed to Fluoxetine suffered from 2 phospholipidosis? There's a difference between 3 something being done and something being 4 reported, Doctor. 5 A. The exact design of the 6 protocol, clinical trial, I'm not -- I don't have 7 the knowledge in detail, and whether that was a 8 part of the protocol or not, I don't recall, I 9 don't know whether that's a part of the protocol 10 in a clinical trial or not. 11 Q. So are you saying you don't 12 know whether or not testing for phospholipidosis 13 was included in protocols or whether a study 14 specifically set up to investigate the 15 possibility of phospholipidosis in humans was put 16 together? 17 A. You're correct. 18 Q. You don't know whether either 19 one of those -- 20 A. I don't know. 21 Q. Have you ever researched it to 22 see if such a study was done? 23 MR. MYERS: Which study? 24 Q. The phospholipidosis. Page 106 1 A. In what? 2 Q. A study looking at the 3 occurrence of or incidence of phospholipidosis in 4 people who were placed on Fluoxetine. 5 A. I'm not in a position to -- I 6 don't know whether that was being done or not. 7 Q. Okay. Have you ever 8 researched it, have you ever specifically gone 9 out and tried to find out if such studies were 10 done? 11 A. I, myself? 12 Q. Yes. 13 A. Not being a clinician, I did 14 not do the research. 15 Q. So Lilly was concerned enough 16 about this issue to go to the FDA with it, 17 correct? 18 A. Repeat again, please. 19 Q. Lilly was concerned enough 20 with the possibility that human beings might 21 suffer from phospholipidosis from ingesting 22 Fluoxetine that they went to the FDA with the 23 issue, correct? 24 MR. MYERS: I object to the form, I Page 107 1 don't think that's why he said they went to the 2 FDA in the first place. 3 MS. ZETTLER: I disagree. 4 Q. You can answer the question. 5 A. The concern is that the 6 finding in animal, the meaning of, and if that 7 would be an obstacle for further development. 8 Q. For the development of the 9 drug? 10 A. Yes. 11 Q. In other words would the FDA 12 prevent you from administering Fluoxetine to 13 humans because of the phospholipidosis that you 14 found in the dog studies? 15 A. Yes. 16 Q. And they said no, they would 17 not prevent you from administering it to humans? 18 A. That's right. 19 Q. Who from the FDA was at this 20 phospholipidosis meeting? 21 A. I don't recall the name of the 22 individuals. 23 Q. Do you remember how many 24 people from the FDA were at the meeting? Page 108 1 A. It was twenty something years 2 ago, I don't recall. 3 Q. How about Doctor Leber? 4 A. He might have been there. 5 Q. Doctor Laughren? 6 A. I don't recall. 7 Q. Temple? 8 A. Maybe Doctor Temple, because 9 the name I heard before. 10 MR. MYERS: Let me caution you, 11 Doctor. If you know or if you recall, tell her, 12 but don't guess just because she suggested a 13 name. If you know, tell her, she's free to 14 suggest names to you. 15 A. I don't recall. 16 Q. Doctor Kapet? 17 A. I don't recall. 18 Q. Hillary Lee? 19 A. I don't recall. 20 Q. Doctor Brecker? 21 A. I don't recall. 22 Q. Doctor Peck? 23 A. I don't recall. 24 Q. David Paul? Page 109 1 A. I don't recall. 2 Q. When was the next time you 3 went to the FDA? 4 A. The second time that I went to 5 FDA was -- that I know the date, October 10, 6 1985. There was the advisory committee meeting 7 on Fluoxetine for indications of depression. 8 Q. And that was held at the FDA? 9 A. Correct. 10 Q. What was your role, if any? 11 A. Again, I was a member of the 12 project team. 13 Q. Did you have any specific role 14 with regards to the meeting itself, did you 15 present information for instance? 16 A. No. 17 Q. Did you answer any questions? 18 A. That I did. 19 Q. What type of questions were 20 you asked? 21 A. One member of the advisory 22 board raised the question at that time that there 23 was a serotonin uptake inhibitor developed and 24 marketed in Europe, developed by Astra, the drug Page 110 1 called Simalodine. The drug produced a flu-like 2 syndrome, and one member of the advisory board 3 raised the question would Fluoxetine would cause 4 flu-like syndrome. 5 Q. And what was your answer? 6 A. And I responded to the 7 question by drawing the structure, comparing the 8 chemical structure between Simalodine and 9 Fluoxetine on the blackboard, pointing out that 10 possibility, the double bond on this chemical 11 structure on Simalodine would be the culprit. 12 Q. Did you present any results of 13 animal studies that you conducted to compare 14 whether or not -- 15 A. That would -- 16 Q. Let me finish my question. 17 Did you report the results of any animal studies 18 that you either did or were aware of that would 19 point to whether or not Fluoxetine would cause a 20 serotonin syndrome like Simalodine? 21 MR. MYERS: I object to the form, he 22 said a flu-like syndrome. 23 Q. Flu-like syndrome. 24 A. I didn't conduct study. Page 111 1 Q. Why not? 2 A. That is observation of Astra's 3 drug, inhibit uptake of serotonin already known 4 to us, so the drug in available such as 5 amitriptyline and imipramine. 6 Q. I'm confused now. 7 MS. ZETTLER: Could you repeat that? 8 (THE COURT REPORTER READ BACK THE 9 REQUESTED TESTIMONY.) 10 Q. So are you saying that since 11 this flu-like syndrome was already associated 12 with Simalodine and other antidepressants that 13 were on the market? 14 A. No. 15 Q. Okay. 16 A. What I was trying to point out 17 is that inhibit uptake is not associated with 18 flu-like syndrome. 19 Q. So the inhibition of serotonin 20 reuptake is not in and of itself associated with 21 the flu-like syndrome? 22 A. Yes. 23 Q. It was a chemical structure of 24 Simalodine that most likely caused the flu-like Page 112 1 syndrome? 2 A. Yes. 3 Q. Did you read any animal 4 studies that were done of Simalodine that 5 indicated that flu-like syndrome was possible? 6 A. I don't recall there's any 7 study being done in the animal could have 8 reproduced the flu-like syndrome of Simalodine as 9 in human. 10 Q. Do you recall what symptoms 11 were associated with that flu-like syndrome? 12 A. I recall was fever. 13 Q. Anything else, nausea? 14 A. Uh-uh. 15 Q. Diarrhea? 16 A. Uh-uh. 17 MR. MYERS: You need to say yes or no 18 just so it's clear. 19 A. No, sorry, no. Achiness. 20 Q. Achiness, muscle aches, joint 21 aches? 22 A. Again, not being a medical 23 doctor, I don't recall the whole spectrum of 24 events that were associated with the flu-like Page 113 1 syndrome. 2 Q. Did you do any independent rat 3 studies with Simalodine comparing it to 4 Fluoxetine to see if the rats had similar 5 reactions to the two drugs? 6 A. As I mentioned, the flu-like 7 syndrome phenomenon of Astra, listed by Astra on 8 its compound, Simalodine, I have yet to see any 9 animal model of that phenomenon. 10 Q. Would it be possible to 11 administer Simalodine to a rat to see what 12 physiological impact the drug had on the rat? 13 A. As I pointed out, that 14 Simalodine's action mainly associated with own 15 structure, and inhibit uptake of serotonin itself 16 is not associated with this flu-like syndrome. 17 Q. Doctor, again, that wasn't my 18 question. Is it possible -- 19 A. That is the reason why I did 20 not conduct those studies to compare. 21 Q. But it is possible to 22 administer Simalodine to the rat to see how it 23 affects the rat psysiologically, correct? 24 A. What do you mean by Page 114 1 psysiologically? 2 Q. Whether or not it affects any 3 of its systems, any of its tissues, and if so, 4 how? 5 A. What particular system? 6 Q. Any systems. You could start 7 out with how the drug affects the organism 8 generally, could you not? 9 A. I don't know what particular 10 system that you had in mind. 11 Q. Any system whatsoever. Just 12 start with the general premise that you could 13 administer Simalodine to the rat to see if it 14 affects any of its systems. Is that true? 15 A. It would inhibit uptake of 16 serotonin. 17 Q. And Fluoxetine given to dogs, 18 it could cause phospholipidosis, correct? 19 A. Yes. 20 Q. In that study was the drug 21 administered to the dogs specifically to see if 22 it would cause phospholipidosis originally or was 23 that an effect that was seen after the 24 administration of the Fluoxetine? Page 115 1 A. That was observed during the 2 toxicological evaluation. 3 Q. So it wasn't like there was a 4 study originally set up that said we're going to 5 give Fluoxetine to the dogs to see if they 6 develop phospholipidosis, correct, this was a 7 finding during the toxicology studies that 8 alerted you that that was a possibility? 9 A. Yes. 10 Q. So could you do a similar 11 study with rats and Simalodine, give them 12 Simalodine and see if it affect any of their 13 systems, examine their systems to see if there 14 were any effects like, for instance, 15 phospholipidosis in rats? 16 A. Is that a question? 17 Q. Yes. 18 A. Whether Simalodine -- 19 Q. No. All I want to know is is 20 it possible to administer Simalodine to a rat and 21 then study generally its effects on the rats? 22 A. Yes, inhibit uptake of 23 serotonin. 24 Q. Could you do a general Page 116 1 toxicology study on a rat to see how the drug 2 affected other systems in its body, say the 3 digestive system or pulmonary system or muscular 4 structure? 5 MR. MYERS: What drug? 6 MS. ZETTLER: Simalodine. 7 A. It's not my interest. 8 Q. I'm asking you if it's 9 possible in the realm of science. 10 A. It's possible. 11 Q. It is possible. And you're 12 saying the reason you did not compare Simalodine 13 with Fluoxetine in rats is because the literature 14 already showed that the flu-like syndrome is not 15 related solely to the uptake or inhibition of the 16 uptake of serotonin, correct? 17 A. Correct. 18 Q. The only evidence that you 19 presented in answer to the question at the 1985 20 advisory committee meeting in response to the 21 Simalodine question was to draw the two chemical 22 structures of each drug? 23 A. To respond to that question, 24 correct. Page 117 1 Q. Any other questions that you 2 were asked? 3 A. I was not asked -- that 4 question wasn't raised to me, it was raised to 5 the team, and I just responded. 6 Q. Okay. Did you respond during 7 the actual meeting or did you respond later in 8 writing? 9 A. I'm sorry? 10 Q. Did you respond during the 11 actual meeting? 12 A. During actual meeting. 13 Q. You got up there in front of a 14 chalkboard and drew the different chemical 15 structures of the two drugs? 16 A. Yes. 17 Q. Any other questions that were 18 asked of the team that you responded to? 19 A. No. 20 Q. What other questions to the 21 best of your recollection were asked during that 22 first meeting in 1985 of the advisory committee? 23 A. That question actually was 24 almost the last question they asked. Page 118 1 Q. Okay. 2 A. And there was not much 3 question asked. 4 Q. Do you recall any other 5 questions that were asked? 6 A. I don't recall it. 7 Q. Any other questions related to 8 animal studies that were asked? 9 A. No, I don't recall. 10 Q. Any questions related to 11 adverse events associated or unassociated with 12 Fluoxetine? 13 A. I don't recall. 14 Q. Did they ask anything about 15 agitation being associated with Fluoxetine? 16 A. I don't recall. 17 Q. Do you recall any other 18 questions or any other subjects that were raised 19 during the meeting? 20 A. The only question that I can 21 recollect is this flu-like syndrome. 22 Q. The one you answered? 23 A. Yes. 24 Q. Prior to that meeting, did Page 119 1 Lilly have any concerns about whether or not the 2 advisory committee would approve Fluoxetine for 3 marketing? 4 A. Would you repeat again, 5 please? 6 Q. Sure. Prior to the meeting, 7 did Lilly have any concerns of whether or not the 8 advisory committee would approve the drug for 9 marketing? 10 A. No. 11 Q. Was any research done as a 12 result of the committee meeting, to your 13 knowledge? 14 A. No. 15 Q. What is the longest period of 16 time that you've had a rat on Fluoxetine? 17 A. Longest time? 18 Q. Right. 19 A. What do you mean by longest 20 time? 21 Q. Time period where you 22 administered it, what's the longest period that 23 you administered Fluoxetine to any particular 24 rat? Page 120 1 MR. MYERS: In his experiment. 2 MS. ZETTLER: Yes. 3 A. You mean every day or -- 4 Q. Right, an hour, a day, a week, 5 a month? 6 A. Up to twenty-five days. 7 Q. Up to twenty-five days? 8 A. Yes. 9 Q. So you have had one rat on 10 Fluoxetine for up to twenty-five days? 11 A. Yes. 12 Q. Twenty-five days being the 13 longest? 14 A. Yes. 15 Q. What was the purpose of 16 putting the rat on Fluoxetine for twenty-five 17 days? 18 A. To study the down regulation 19 of receptors. 20 Q. What is a rat day? 21 MR. MYERS: I object to the form 22 because I have no idea what you mean. 23 Q. Like in other words, is a day 24 for a rat a twenty-four hour period like it is Page 121 1 for humans or is it a different time frame in 2 research? 3 A. The rat day? 4 Q. Right. 5 A. The rat is a nocturnal animal. 6 Q. You got me into this, you get 7 me out of it. How about a rat night? No, 8 seriously, is there a certain period of time 9 that's considered a day for a rat as opposed to a 10 twenty-four hour period for human beings? 11 A. We arbitrary set the light on 12 6:00 p.m. -- no, 6:00 a.m., and turn the light 13 off 6:00 p.m. 14 MR. SMITH: Let me interrupt. The 15 reason we're asking that is because the normal 16 life span of a rat is different from the normal 17 life span of a human, obviously. 18 THE WITNESS: Yes. 19 MR. SMITH: And what is the 20 correlation between a normal life span of a rat 21 versus the human, and how does that equate to 22 days with respect to research in animals and 23 drawing any kind of conclusion in connection with 24 a particular effect of a particular drug? Excuse Page 122 1 me for that interruption. 2 MR. MYERS: Do you understand what 3 he's getting at? 4 A. I think that I can answer the 5 life span of a rat. 6 MR. MYERS: Start with that. 7 A. The life span of a rat is 8 average between twenty-five and twenty-seven 9 months. 10 Q. Let me start it this way: 11 When you say you had a rat on Fluoxetine for 12 twenty-five days, are you talking about 13 twenty-five twenty-four hour periods of time? 14 A. Our days, yes. 15 Q. Okay. Now, do you have to 16 figure out -- like for us, twenty-five days is 17 twenty-five days, okay, almost a month. Now as 18 Paul pointed out earlier, twenty-five days in a 19 rat life is a much larger comparative chunk of 20 time. Do you understand what I'm saying? 21 MR. MYERS: To the life span of the 22 rat. 23 Q. To the life span of the rat as 24 it is to the life span of a human, right? Page 123 1 A. Yes. 2 Q. Do you have to somehow 3 extrapolate from putting a rat on twenty-five 4 days saying that it's equivalent to say five 5 years for a human being, could you do that? 6 A. No, I did not make that 7 extrapolation. 8 Q. Do you know of anybody who has 9 made that extrapolation, with regards to rats and 10 Fluoxetine? 11 A. I don't know. 12 Q. You testified last time that 13 the only animal studies that you performed with 14 regards to Fluoxetine are rat studies, correct? 15 A. Yes. 16 Q. Are you aware of any other 17 animal studies that were performed at Lilly on 18 Fluoxetine other than rat studies? 19 A. Mice. 20 Q. Any others? 21 A. Are we talking about basic 22 studies? 23 Q. Start with basic studies. 24 A. Rat and mice. Page 124 1 Q. Rat and mice. Let's go to any 2 other, not behavioral, but physiological studies 3 done at Lilly on other animals, like for instance 4 we know the dog studies were done, correct? 5 A. Uh-huh. 6 Q. Toxicology studies on dogs, 7 right? 8 A. That's toxicology studies, 9 yes. 10 Q. I'm talking about any 11 physiological as opposed to any behavioral study, 12 okay. Are you aware of any other studies besides 13 rat studies, mice studies, dog studies? 14 A. I'm aware of cat studies. 15 Q. Okay. Any others? 16 A. Dog study. 17 Q. Dog. 18 A. Uh-huh. 19 Q. How about chick studies? 20 A. Chicks, I don't recall. 21 Q. Monkeys, from a physiological 22 standpoint at this point. 23 A. Well, to me is biochemical. 24 Q. You could have a physiological Page 125 1 study, a toxicology study, right, done, you could 2 have a behavioral study done, you could have a 3 combination of the two done, right? 4 MR. MYERS: Let me object to the form. 5 Are you equating physiological with toxicology 6 because -- 7 Q. I'm talking about something 8 that studies the physiological aspect of the 9 organism as opposed to the behavioral aspect of 10 the organism, either the toxicology study, the 11 drug's impact, you know, as far as toxicology, or 12 just the general studies like he did where you 13 study to see whether or not there's an impact on 14 the reuptake the of serotonin, okay. I just want 15 to know the categories of animals that you were 16 aware of where some sort of study with a 17 physiological impact to it or a physiological 18 bent to it was done. I know you talked about 19 rats, mice, dogs and cats. 20 A. Yes. 21 Q. Do you know of any toxicology 22 or other physiological type studies that were 23 done on monkeys with Fluoxetine? 24 A. Are you talking within Lilly? Page 126 1 Q. Yes, we'll start with Lilly. 2 A. I don't recall. 3 Q. Any other animals that you can 4 recall where physiological-type studies were done 5 on animals at Lilly? 6 A. That's all I can remember. 7 Q. Okay. How about behavioral 8 studies that were done at Lilly on animals? 9 A. In rats. 10 Q. Okay. 11 A. In mouse. 12 Q. Okay. 13 A. That's all I can remember. 14 Q. Cats? 15 A. Depend where you draw a line 16 between what is physiology and which is behavior. 17 Q. Purely behavioral studies. 18 Not a physiological study where some strange 19 behavior was observed by happenstance. 20 MR. MYERS: You want to know where the -- 21 an objective of the study was to observe -- 22 Q. The behavior of the animal. 23 A. No. 24 Q. Monkeys? Page 127 1 A. Within Lilly, no. 2 Q. Dogs? 3 A. Behavior in dogs, no. 4 Q. Are you aware of any studies 5 done at Lilly on animals with a physiological 6 bent, either a toxicology study or other 7 physiological studies, like for instance your 8 studies, where somebody has observed unusual 9 behavior, just by happenstance, not by a goal of 10 a study? 11 MR. MYERS: When you say physiological 12 bent, again, where the objective was to study 13 some physiological change other than some kind of 14 behavioral change. 15 MS. ZETTLER: Right, behavioral change 16 became apparent. 17 A. Will you repeat again, please? 18 Q. I'm trying to find out if 19 there were any studies that were done at Lilly on 20 animals with a physiological bent, either a 21 toxicology study or other study of physiological 22 impact of the drug on the animal, you know, not a 23 behavioral study, but a study that's looking at 24 the physiological aspects of the impact of the Page 128 1 drug where an unusual behavior was observed, not 2 as part of the study, but happened to crop up? 3 A. Since my emphasis is mainly 4 more in line with basic research, and my 5 awareness of the toxicological study may not be 6 complete, and as far as I know, I have not -- I'm 7 not aware of untoward behavioral effect. 8 Q. Are you aware that there was a 9 study done by Lilly on rats where the rats showed 10 hyperirritability? 11 MR. MYERS: I object to the form only 12 to the extent I don't know -- you haven't 13 provided much of a description of the study, and 14 I don't know even if you have that the outcome 15 has been scientifically described precisely. But 16 if you know of such a study, tell her if you're 17 aware. 18 A. Could you repeat, please? 19 Q. Yes. Are you aware of any rat 20 studies that were performed at Lilly where the 21 rats in the study became irritable, exhibited 22 hyperirritability? 23 MR. MYERS: Same objection. If you 24 know, tell her. Page 129 1 A. I'm not aware of. 2 Q. Are you aware of any studies 3 whatsoever done at Lilly on animals with 4 Fluoxetine where any of the animals showed any 5 strange behavioral changes, whether or not those 6 were being looked at in the study or not? 7 MR. MYERS: Whether it was a 8 behavioral or a physiological study this time? 9 MS. ZETTLER: Right, the whole gamut. 10 A. The only incident that I 11 recall was in a cat, and the cat maybe more 12 excited. 13 Q. Was this a behavioral study or 14 toxicology study or other type of study? 15 A. That was monitor of the sleep 16 EEG study. 17 Q. Is that the REM sleep study? 18 A. Yes. 19 Q. And this was on cats, right? 20 A. Yes. 21 Q. And when you say they became 22 excitable, what do you mean? 23 A. Since I'm not the person who 24 handled the animal -- Page 130 1 Q. Tell me what your 2 understanding is of what happened to the cat on 3 the study. 4 A. That's the understanding that 5 I get from the person who handled the cat. 6 Q. Was it one cat or more than 7 one cat? 8 A. I don't know how many cats. 9 Q. Who handled the cat? 10 A. I only remember his first 11 name, Tom. At the time he was reporting to 12 Doctor Slater. 13 Q. Is Tom still with Lilly to 14 your knowledge? 15 A. No. 16 Q. Do you know where Tom went? 17 A. I believe he retired. 18 Q. Was he an older gentleman? 19 A. Yes. 20 Q. What was his position at 21 Lilly? 22 A. He's associate, reports to 23 Doctor Slater. 24 Q. Associate? Page 131 1 MR. MYERS: He was an associate 2 reporting to Slater, is that what you said? 3 THE WITNESS: Yes. 4 Q. When you say associate, what 5 do you mean? 6 A. He worked in Doctor Slater's 7 lab. 8 Q. Was he a research associate? 9 A. He's a -- 10 Q. Was he conducting the study or 11 was he feeding the cats and cleaning out their 12 cages? 13 A. Well, he's the one that, with 14 Doctor Slater's instruction and to monitor the 15 sleep EEG pattern. 16 Q. So he was actually helping 17 Doctor Slater perform the test? 18 A. Yes. 19 Q. Okay. What did he tell you 20 about the cats? 21 A. That these -- what I 22 mentioned, is more excited. 23 Q. More excited? 24 A. Yes. Page 132 1 Q. Did he say whether they became 2 aggressive? 3 A. That, I don't recall being 4 mentioned. 5 Q. In the scientific community 6 are the results of cat studies as easily 7 extrapolated to impact on humans as rats or mice 8 studies? 9 MR. MYERS: I object to the form only 10 to the extent you assume it is easier to 11 extrapolate rats and mice. 12 A. Since cat is not the animal I 13 use, that never really cause me to extrapolate. 14 Q. Research is performed on rats 15 and mice because there are correlations between 16 their physiological make up and our physiological 17 make up, correct? 18 A. The reason why -- the reason 19 why rat and mouse being used is they are more 20 readily reproduced. 21 Q. But are there other 22 similarities between their physiological make up 23 and ours? 24 A. They have comparable enzymes Page 133 1 and physiological processes. 2 Q. Not all animals in the entire 3 spectrum of animals are used for experimentation 4 with drugs that are to be used on humans, 5 correct? 6 A. That limited -- the other 7 species would be limited to supply and also cost. 8 Q. But generally the animals that 9 drugs are tested on are rats, mice, monkeys, 10 organisms that are closer to our own than, say, a 11 snake or a frog? 12 MR. MYERS: When you say tested, for 13 what purposes? 14 MS. ZETTLER: Physiological tests. 15 A. Rats and mouce are more 16 regularly used. 17 Q. How is it that scientists feel 18 confident to extrapolate the effect of a drug on 19 a mouse to its effect on human beings? 20 MR. MYERS: I object to the form only 21 because I don't know that he's testified to that. 22 MS. ZETTLER: That's why I'm asking 23 him now, Larry. 24 MR. MYERS: You stated it as a fact as Page 134 1 opposed to asking him, that's the problem with 2 the question. 3 MS. ZETTLER: I think the last time he 4 testified that the results of at least his 5 studies were extrapolated to be similar in humans 6 as far as the serotonin reuptake inhibition of 7 Fluoxetine. 8 MR. MYERS: If he said it, let's get 9 it out and see where it was, and maybe that -- 10 Q. Are you saying that there was 11 no way to extrapolate from what you found as far 12 as Fluoxetine's ability to inhibit the reuptake 13 of serotonin in mice or rats to its impact on the 14 serotonin system of human beings? 15 A. I can only say that Fluoxetine 16 inhibit uptake of serotonin in rat, and in rat 17 brain. 18 Q. But somebody somewhere along 19 the line made the assumption that if it did it in 20 rats it would do it in people, didn't they? 21 A. If that pathway is equally 22 important in human. 23 Q. Is there any evidence that the 24 pathway is equally important in humans? Page 135 1 A. Or the pathway have relevance 2 in animal -- in human, mental illness in human. 3 Q. Let's go back to my first 4 question. Is there any evidence that the pathway 5 in mice is equal to the pathway in humans? 6 A. The path -- the component 7 enzymetic components in rat also -- or I should 8 say in human also present in rats. 9 Q. So you can at least start with 10 a similarity between the pathways, correct? 11 A. Yes. 12 MR. HARRIS: Is serotonin an enzyme? 13 THE WITNESS: The enzymes to make 14 serotonin -- 15 Q. Enzymes take the amino acid of 16 L-tryptophan and create serotonin from that? 17 A. Yes, for the synthesis of 18 serotonin. 19 Q. What enzyme is that? 20 A. Tryptophan hydroxylase, amino 21 acid decarboxylase. 22 Q. Besides the amino acid in 23 L-tryptophan, is there any other enzymes or 24 anything else that is needed to synthesize or Page 136 1 create serotonin in the brain? 2 A. Those are the two enzymes. 3 Q. So it's the tryptophan itself 4 and the two enzymes? 5 A. Tryptophan hydroxylase. 6 Q. That's the enzyme or that's 7 the tryptophan -- or that's the amino acid? 8 A. The first step is tryptophan 9 hydroxylase to hydroxolize tryptophan. 10 Q. So you have tryptophan, which 11 is the amino acid? 12 A. Yes. 13 Q. You have the tryptophan 14 hydroxylase -- 15 A. Yes. 16 Q. -- that is the first -- 17 A. Enzyme. 18 Q. -- enzyme that works on the 19 tryptophan. 20 A. Yes. 21 Q. And then there's another 22 enzyme that also works on the tryptophan to 23 create -- 24 A. The other enzyme is work on Page 137 1 the hydroxylase of tryptophan. 2 Q. So it works on the product of 3 the tryptophan hydroxylase reacting with the 4 tryptophan? 5 A. Correct. 6 Q. After that, the second enzyme 7 that works on the product from the tryptophan in 8 the first enzyme is the serotonin? 9 A. Correct. 10 MR. MYERS: Mister Smith established 11 that all last time, I'm sure he recalls it in 12 great detail. He proved it. 13 MS. ZETTLER: Is that an admission, 14 Larry? I think it's time to go to lunch. 15 MR. MYERS: Do you want to break here? 16 MS. ZETTLER: Yes. 17 (A SHORT LUNCH RECESS WAS TAKEN.) 18 Q. (BY MS. ZETTLER) Doctor, 19 before we broke for lunch, you told us a little 20 bit about a rat study you did on down regulation 21 where you had rats on Fluoxetine for up to 22 twenty-five days. 23 A. Yes. 24 Q. Is that one study or have you Page 138 1 done multiple studies on down regulation? 2 A. Multiple studies. 3 Q. How many studies have you done 4 on down regulation? 5 A. Probably about six. 6 Q. Okay. All on rats? 7 A. Yes, uh-huh. And published in 8 two separate papers, I believe. 9 Q. All six studies were published 10 in two separate papers? 11 A. Yes. 12 Q. When did you first do a down 13 regulation study on rats, your first study? 14 A. In 1982 or something like 15 that. 16 Q. What prompted you to do the 17 first study? 18 A. That's one of the things I 19 thought maybe a criteria for how clean the 20 Fluoxetine is, how selective Fluoxetine is. And 21 this is such a thing as the positicity of the 22 neuron that is -- the system neuron able to up 23 regulate or down regulate their receptors, able 24 to adjust according to the impact of changes in Page 139 1 the transmission of a neurotransmitter. 2 Q. So what the impact on the 3 changes of a neurotransmitter were on the 4 receptor neurons? 5 A. Yes, the receptor of the 6 neuron. 7 Q. So that's two criteria. Was 8 there any more, any other reasons? 9 A. That was major reason. And 10 also want to know the consequence of the 11 inhibition uptake of serotonin in terms of there 12 is effect on the adaptive change on the receptor 13 of serotonin. 14 Q. So the consequence of the 15 inhibition of serotonin uptake on the adaptive 16 abilities of the serotonin receptor? 17 A. Adaptive, yes, uh-huh. 18 Q. Okay. So let me make sure 19 I've got these straight, okay. One of reasons 20 you did the first study was to see how selective 21 Fluoxetine really was, right? 22 A. Yes. 23 Q. The second reason was to see 24 what the impact of the inhibition of reuptake of Page 140 1 serotonin was generally on the neuron, the 2 receptor? 3 A. Uh -- 4 Q. Or wait, let me ask -- I think 5 I got confused. The second reason was to see 6 what the impact of Fluoxetine was on the receptor 7 neuron? 8 A. The impact of the inhibition 9 of uptake of serotonin on the adaptive change. 10 Q. Okay. That was the third one. 11 There was another one, weren't there three? 12 A. There was two. 13 Q. Okay. So two reasons, how 14 selective Fluoxetine really was in inhibiting 15 just serotonin and not other neurotransmitters, 16 right? 17 A. Yes. 18 Q. Okay. And the effect or the 19 consequence of the inhibition of serotonin uptake 20 on the adaptive abilities of receptor neurons? 21 A. The receptor of serotonin. 22 Q. Okay. Is this something that 23 you just decided to do on your own or is this 24 something somebody else at Lilly asked you to do? Page 141 1 A. Relatively on my own. 2 Q. And that strictly limited the 3 first study or just down regulation studies in 4 general that you did? 5 MR. MYERS: When you say this -- 6 Q. The reasons that they were 7 done. 8 A. This study addressed both 9 questions. 10 Q. But I'm saying, you said 11 earlier that you did six studies related to down 12 regulation, right? 13 A. Yes. 14 Q. Did you do all those studies 15 because of these two reasons that you just set 16 out? 17 A. Yes. 18 Q. And the first one was done in 19 1982, correct? 20 A. It was beginning around that 21 time, in 1982. 22 Q. Approximately? 23 A. Yes. 24 Q. Did you run more than one Page 142 1 study at a time? 2 A. No, no. 3 Q. Tell me about the first study. 4 MR. MYERS: What about it? 5 Q. Generally give me an idea of 6 what it was, I mean how long did you put them on 7 Fluoxetine, did you do the in-dwelling probe 8 study or did you do sacrifice or whatever, just 9 give me a general idea of how the study was 10 structured. 11 A. Treat the rat for initially, I 12 believe, it was twenty-one days. 13 Q. Okay. 14 A. And then at the end of the 15 study, we killed animal and take the brain tissue 16 out, disect the brain, particularly in the 17 frontal cortical area of the brain. And we would 18 do binding of radioligand -- 19 Q. I'm sorry, binding of what? 20 A. Radioligand, radioactive 21 ligand. Means -- ligand is a molecule at the top 22 of the particular site. 23 Q. Go ahead, I'm sorry. On how 24 many rats did you have on this first study, do Page 143 1 you remember? 2 A. There's a control treated 3 group which is using saline solution, which is 4 zero point nine percent sodium chloride solution. 5 That's one group, we give the injection daily. 6 And then there is another group of about -- of 7 Fluoxetine treated, and mostly between eight 8 animal to twelve animals. 9 Q. Eight in the control and 10 twelve in the active? 11 A. I'm sorry? 12 Q. Eight in the control group and 13 twelve in the Fluoxetine group? 14 A. No, eight in a control and 15 eight in the Fluoxetine group. 16 Q. Okay. So it's eight in the 17 control and eight in the other. 18 A. Yes. Near those numbers. 19 Q. So from like eight to twelve, 20 depending on the study? 21 A. Yes. 22 Q. Let me back up a little bit. 23 What is down regulation? 24 A. A personal opinion, okay, Page 144 1 based on -- 2 Q. I'm just asking for your 3 understanding. 4 A. The adaptive change of a 5 receptor have to do with a persistent duration of 6 the receptor by the neurotransmitter, whether 7 it's serotonin or norepinephrine, and the neuron 8 have the mechanism to reduce the number of the 9 receptor that become available if there is 10 sufficient transmission take place. 11 Q. Are you done? 12 A. Yes. 13 Q. Let me make sure I understand 14 you. Does this have anything to do with the 15 firing of the receptor neuron? 16 A. Yes. 17 Q. Okay. So from a layman's 18 standpoint, and trust me, I'm a layman on this. 19 A. No problem. 20 Q. If you're saying that -- for 21 instance, if you have Fluoxetine that's been 22 administered, and the reuptake is being blocked, 23 and there's more serotonin that's available in 24 the cleft or the same amount of serotonin for a Page 145 1 longer period of time, that the neuron is going 2 to continue to fire as long as the serotonin is 3 there to cause it to fire, correct? 4 A. Yes. 5 Q. Now, down regulation is the 6 neuron itself adjusting for the constant effect 7 of the serotonin to fire less often? 8 A. No, the receptor responds to 9 the presence of the transmitter. 10 Q. The what? 11 A. Presence of the greater of 12 ability of the transmitter -- okay, this is a 13 synapse. 14 Q. Okay. 15 MR. SMITH: Have him draw it. 16 Q. Is that okay with you? 17 A. Yes. And this is a nerve 18 terminal, assume. And we have attached to a 19 adjacent cell, adjacent neuron, adjacent nerve 20 cell. So if this is the serotonin neuron, could 21 be norepinephrine neuron as well -- 22 Q. Let me just real quick 23 interrupt you because there's something I'm not 24 quite sure of. When you say serotonin producing Page 146 1 or storing cell, are you talking about the 2 serotonin neuron? 3 A. Yes. Serotonin is also called 4 5-HT. 5 Q. Right. 6 A. So when the nerve impulse is 7 publicated, that is this neuron get a signal from 8 this mother parent cell, okay -- let me give it a 9 more vivid illustration. The serotonin neuron is 10 in the back behind brain. 11 Q. Okay. 12 A. Here this terminal is -- this 13 axon extend to various area in the brain from 14 behind brain. 15 Q. Are you saying axium? 16 A. Axon. 17 Q. How do spell that? 18 A. A-X-O-N. So that could be 19 cortical area or hippocampal area or whatever. 20 Q. But they all originate from 21 the back of the brain? 22 A. Yes, the serotonin cell 23 bodies. So when that signal is publicated along 24 this axon it will release serotonin, okay, and Page 147 1 that would activate the receptor, okay. 2 Q. So this is the receptor neuron 3 here? 4 A. Yes. 5 Q. Could you mark that with 6 number one? 7 A. We'll call this postsynaptic. 8 Q. Okay, that's fine. 9 A. And then we also have -- this 10 is uptake of serotonin, this is uptake site for 11 serotonin, and being reuptake, okay. And drug 12 like Prozac would block this reuptake. So that 13 makes this more available. 14 Q. Okay. So the serotonin that's 15 produced by the cell stays in the synaptic cleft 16 longer before it's taken back up into -- 17 A. Yes. 18 Q. Sometimes it's not even taken 19 back up with the Fluoxetine, correct? 20 A. Eventually it would be taken 21 up. 22 Q. Okay, so when you talk -- 23 A. Then this receptor receiving 24 this molecule serotonin, and the constant Page 148 1 activation -- this receiving process we call 2 activation, activating receptor, because after 3 receiving serotonin, there will be a signal 4 publicate, okay -- 5 Q. Causing the neuron to fire or 6 whatever. 7 A. Calcium relieves to produce 8 other signals inside the neuron to produce 9 whatever it needs to do. 10 Q. So in other words it causes 11 this neuron to do whatever it needs to do for 12 different processes in the body, like you talked 13 about last time, hunger -- 14 A. Yes, release of peptides or 15 hormones, whatever. So this activation process, 16 if it's consistent -- persistent, this receptor 17 would readjust itself. So the readjustment is 18 called regulation. If the receptor number went 19 up, we call up regulation. Up regulation is only 20 when situation that is insufficient amount of 21 suppliers of transmitter occur. 22 Q. Insufficient amount of suppy? 23 A. Yes, most situation. But a 24 down regulation is the persistent activation of Page 149 1 that receptor occur, and then the -- this is a 2 membrane, okay, just like skin of a cell, all 3 cells have skin. So this launch within the 4 membrane domain and would -- the molecule, 5 receptor, like gymnastic, having a tumbling 6 occur, and so it would face in, face out, 7 depending on whether up regulate or down 8 regulate. So when receptor is being persistently 9 activated, then it would down regulate. 10 Q. What is -- I've seen a lot of 11 references to firing of neurons? 12 A. Uh-huh. 13 Q. What is that? 14 A. That -- the cell here is the -- 15 that is the releasing mechanism. 16 Q. What do you call what happens 17 on this end with the receptor? Just makes it -- 18 does it start a chemical reaction or start some 19 sort of reaction that produces peptides and 20 things of that nature? 21 A. Well, there are so many 22 consequences that we are beginning to appreciate, 23 but to that receptor, it's just receiving more 24 signal from this synapse. Page 150 1 Q. Is there a term of art for the 2 reception of the signal and the consequence of 3 the reception of the signal, like neurons firing? 4 A. Oh, yes. This signal that 5 would stimulate this neuron to fire. 6 Q. So it is a firing of a neuron, 7 too? 8 A. Yes. 9 Q. So the firing back here when 10 the cell produces serotonin, and you have a 11 firing on this end when the serotonin affects the 12 receptor? 13 A. Yes, this is the receiving 14 end. 15 Q. I'm not as confused as I 16 thought. Now what causes the cell, the serotonin 17 cell or neuron in the back of the head to fire to 18 cause the neuron-producing cell to make -- or the 19 serotonin-producing cell to make serotonin? 20 A. What causes it, that's a very 21 good question. 22 Q. Does anybody know? 23 A. I would love to know. 24 Q. Have you ever seen any Page 151 1 research that's been done to find that out? 2 A. Definitely there's an arousal 3 process, there are a degree of our awakening that 4 control the firing. And that is one way that 5 this cell body of serotonin responsive to arousal 6 stimulant. 7 Q. So if we are affected by a 8 stimulant, it may cause the serotonin to be -- 9 A. My react response to you, this 10 moment, I'm sure there's a lot of the serotonin 11 firing. 12 Q. I'm not going to ask you why. 13 MR. MYERS: Don't say anything. 14 Q. Okay. Is there any evidence 15 that the metabolizing of serotonin has anything 16 to do with the firing of the serotonin-producing 17 cells in the back of the brain? 18 A. Repeat again, please. 19 Q. Sure. Do you know of any 20 evidence that the metabolizing of serotonin 21 that's produced, you know, the serotonin that's 22 produced put into the synaptic cleft and then 23 metabolized has anything to do with the 24 production of serotonin in the back of the brain? Page 152 1 A. What happens is the serotonin 2 release in the synaptic cleft and it would 3 normally be taken up. And then the serotonin 4 could get back to the outside -- the inside of 5 the synapse, and the enzyme within the synapse, 6 this terminal, would destroy the serotonin to 7 form the metabolite. 8 Q. Right. But my question is if -- 9 A. It doesn't produce firing 10 effect is all you're asking. 11 Q. Yes, the firing effect of the 12 serotonin cells in the back of the brain. 13 A. Does the metabolite produce 14 firing? 15 Q. That's my question, does it? 16 A. I don't believe so. 17 Q. Is there evidence that it does 18 not? 19 A. It doesn't, yes, there is 20 evidence that it doesn't, the metabolite doesn't 21 fire. 22 Q. But it doesn't send a signal 23 back to the back of the brain that we need more 24 serotonin, we used up what we have here? Page 153 1 MR. MYERS: The metabolite? 2 MS. ZETTLER: Right. 3 Q. Do you see what I'm trying to 4 get at? 5 A. Yes, I believe so. I don't 6 recall any responsiveness to the metabolite. 7 Q. Let me ask it this way -- 8 A. Metabolite is something -- 9 Q. It's a waste product? 10 A. Yes. 11 Q. Let me ask it this way: You 12 testified last time, and our basic understanding 13 is that Fluoxetine blocks the reuptake of 14 serotonin back into the serotonin storing or 15 producing cell, right? 16 A. Yes. 17 Q. Leaving the serotonin that's 18 produced by the cell in the synaptic cleft longer 19 to affect the receptor neuron, right? 20 A. Yes. 21 Q. If the receptor neuron is 22 firing because the serotonin is in the cleft, the 23 synaptic cleft, does that send a message to the 24 back of the brain not to produce anymore Page 154 1 serotonin, we have enough? 2 A. I think so, yes, it has a 3 self-regulating. 4 Q. Like the homeostasis we were 5 talking about last time? 6 A. Yes. 7 Q. Does anybody know how long 8 serotonin is effective in the synaptic cleft once 9 it's distributed there? 10 MR. MYERS: Let me just interject or 11 ask, when you say effective, effective for what 12 purpose? 13 Q. For causing the receptor 14 neuron to fire. How long is it -- is it 15 effective for weeks, is it effective for a couple 16 of hours, I mean obviously it's got a purpose, 17 right, the serotonin has a purpose, correct? 18 A. I hope so. 19 Q. I hope so or we're all out of 20 business, right? Serotonin has an effect? 21 A. Yes. 22 Q. And that effect is to cause 23 the receptor neuron to fire, correct? 24 A. Yes. Page 155 1 Q. Serotonin is a chemical? 2 A. Correct, a neurotransmitter. 3 Q. How long does that chemical 4 work, in other words how long can it stay in the 5 synaptic cleft and cause this receptor to fire? 6 A. At this point, technically 7 it's almost impossible to demonstrate, to 8 investigate. 9 Q. Okay. 10 A. We have not reached that 11 technical resolution. 12 Q. Do you have any idea, do you 13 have an opinion as to how long it would last? 14 A. The only way one can make some 15 estimatation is what happened when we studied the 16 radioligand binding to the receptor, and you can 17 study the binding or the rate of association, 18 after binding, and that's also a rate of 19 disassociation. So this is a constant binding, 20 association and disassociation continuously going 21 on. So there's that kind of very opportune 22 artificial way to address the question that you 23 raised. 24 Q. Okay. Page 156 1 A. And so it's difficult to tell 2 just doing that, to say how long the serotonin in 3 the synapse could be there to exert this effect. 4 Q. Okay. Is it possible for 5 Fluoxetine to completely block the uptake of 6 serotonin? 7 A. In my experience, studying 8 animal system, and we have yet to reach total 9 inhibition, so I can only give that you that 10 experience, tell you that experience. 11 Q. Okay. Is that measured by the 12 metabolite? 13 A. No. 14 Q. Is that measured by the 15 binding and grinding and radioactive -- 16 A. Acute uptake of radioactive 17 serotonin. 18 Q. Can you quantify for me what 19 the greatest level of inhibition you have found 20 has been? 21 A. In a test tube, in a test 22 tube, you can reach as much about ninety percent 23 inhibition. 24 Q. Okay. Page 157 1 A. So what happens is there is an 2 equalibrium, again, go back to the association, 3 disassociation process. So theoretically it's 4 difficult to reach -- it's a competitive process, 5 it's difficult to reach a complete inhibition. 6 Q. But the best you've done in a 7 test tube is ninety percent? 8 A. Yes. 9 Q. How about in a living organism 10 like a rat? 11 A. I have yet to observe greater 12 than eighty percent inhibition, ex vivo, what we 13 call ex vivo. 14 Q. Ex vivo is when you sacrifice 15 the animal and you study the brain after it's 16 been sacrificed. 17 A. After the animal been treated 18 and sacrificed and harvesting the nerve ending to 19 do the patient. 20 Q. When you say patient, you mean 21 rats, right? 22 A. I didn't say patient. 23 Q. You didn't say patient, what 24 did you say? Page 158 1 A. After treating animal and 2 sacrifice animal, disect and take the nerve 3 ending preparation. I think I said preparation. 4 Q. Was it preparation? So you 5 don't ever refer to your rats as patients? 6 A. No. 7 Q. I thought I must have 8 misunderstood you because I thought you said 9 you've yet to see in patients exvivo? 10 MR. MYERS: No more than eighty 11 percent, maybe that's what you heard him say. 12 Q. I just wanted to make sure 13 we're still talking about rats and not human 14 beings, that's all. 15 A. Correct. 16 Q. Let me back up again a little 17 bit further. Is L-tryptophan the amino acid that 18 the serotonin producing cell needs to produce 19 serotonin in rats as well as humans? 20 MR. MYERS: Do you mean L-tryptophan 21 or tryptophan? 22 MS. ZETTLER: Tryptophan, right. 23 A. It is the L isomer of 24 tryptophan being used as a precursor of amino Page 159 1 acid for the synthesis of serotonin. 2 Q. Can we just call it tryptophan 3 just to shorten it a little bit? 4 A. Okay. 5 Q. So tryptophan is necessary in 6 both rats and in human beings to produce 7 serotonin, or at least a part of what is 8 necessary? 9 A. Yes. 10 Q. Are the enzymes that we talked 11 about earlier, are those enzymes the same, the 12 ones that work on the tryptophan to produce 13 serotonin, are those enzymes the same in rats and 14 in humans? 15 MR. MYERS: When you say the same, you 16 mean are they present in some -- 17 Q. Right. Obviously the 18 tryptophan has to be synthesized to become 19 serotonin, right? 20 A. Well, the process is the same. 21 Q. Okay. 22 A. But the enzyme may not exactly 23 be the same. 24 Q. Are they similar? Page 160 1 A. They are have high homology, 2 amino acid homology. 3 Q. But still, as far as the 4 process of synthesizing the tryptophan to become 5 serotonin, you're confident that the two 6 processes in rats and humans are close enough 7 that you can extrapolate? 8 A. They're similar process. 9 Q. Similar enough so that you 10 can, again, somebody can extrapolate what happens 11 with the rat's serotonin producing system may 12 happen with a human being's serotonin producing 13 system? 14 A. Yes, I think so. 15 Q. How about the neurons, are the 16 structure of the neurons similar between rats and 17 humans? 18 A. I don't have human brain to 19 work with, and so I cannot make that comparison. 20 Q. Do you know if the serotonin 21 neurons originate from the brain stem of a rat 22 like they do in humans or the back of the brain? 23 A. Behind the brain in a rat 24 brain. Page 161 1 Q. In both human and the rat 2 brain? 3 A. Yes. 4 Q. And in your opinion is the 5 process, in other words, the cells that fire to 6 command the serotonin producing cells to produce 7 serotonin, is that generally the same structure 8 and the way it works generally the same with the 9 rat as it is with the human being? 10 A. I don't know completeness of 11 this similarity, but the process for synthesis of 12 serotonin are similar or comparable. 13 Q. Have you ever done a study or 14 seen a study where, like, L-tryptophan or 15 proteins that contain tryptophan are administered 16 or given to patients to see if their serotonin 17 level increases? Remember we talked the last 18 time about the Charney study, I believe it was, 19 where the people that were on Desipramine and 20 Fluoxetine were then given a tryptophan deprived 21 drink? 22 A. Yes. 23 Q. Have you ever seen the 24 opposite, where people were given a tryptophan Page 162 1 enriched drink or meal to see if that has an 2 effect on the serotonin level? 3 A. Since you mentioned the change 4 in serotonin level, as I mentioned, it is very 5 difficult to monitor the level of serotonin in 6 the brain. 7 Q. So an effect on serotonin, the 8 process? 9 A. Perhaps the question needs to 10 be more precise, and see if we can take that. 11 Q. We know that tryptophan is an 12 essential amino acid that's necessary to produce 13 serotonin, right? 14 A. Yes. 15 Q. Obviously different people 16 have different types of diets, correct? 17 A. Yes. 18 Q. And some people like, say, in 19 Bosnia are not getting as much food as we are and 20 theoretically aren't getting as much protein, 21 they may be producing less serotonin because of 22 that lack of protein and tryptophan, correct? 23 A. Yes. 24 Q. And there is also a theory -- Page 163 1 you want to say something? 2 A. Protein is only one of the 3 source. 4 Q. Right. I'm just trying to 5 generalize it as much as possible to make it 6 simple. One of the theories, and the theory that 7 you based a lot of your research on was that of 8 decreased activity or level of serotonin was 9 related to depression, correct? 10 A. No. 11 Q. No? 12 A. The decrease in dysfunction of 13 the neuron. 14 Q. Dysfunction of the receptor 15 neuron or the producing neuron? 16 A. The serotonin containing 17 neuron. 18 Q. Dysfunction how, like 19 inability to produce serotonin? 20 A. That is a current research 21 area, trying to delineate what is limiting. 22 Q. So there is some reason the 23 serotonin-producing or containing cell is not 24 putting out either enough serotonin or serotonin Page 164 1 that is effective enough in firing the neuron? 2 A. Yes. 3 Q. Have there been any studies 4 that you're aware of or have done yourself that 5 relate a decreased intake of tryptophan with 6 either not enough serotonin being produced or 7 deficient serotonin being produced, deficient 8 meaning not active enough? 9 MR. MYERS: Study in what model? 10 Q. Any model whatsoever. Are you 11 aware of any study whatsoever that has tried to 12 look at a decreased level of tryptophan being 13 related to a dysfunction in the serotonin 14 producing cell of some sort? 15 A. In animals, in treated with 16 inhibitor of tryptophan hydroxylase, and which 17 ultimately would lower the brain concentration of 18 serotonin in rats, for instance, that have been 19 done. 20 Q. So there is a correlation 21 between either the lack of presence of tryptophan 22 or the inability of the body to synthesize the 23 tryptophan into serotonin that has been made with 24 the decrease in the function of the serotonin Page 165 1 producing cells? 2 A. The study was to reduce the 3 serotonin concentration in the rat brain after 4 treating animal with the inhibitor of the enzyme 5 that's hydroxolyzed tryptophan. 6 Q. So even if the tryptophan is 7 there, it can't be synthesized properly? 8 A. When the inhibitor is there, 9 that tryptophan cannot be -- 10 Q. It interferes with the 11 synthesis of the tryptophan? 12 A. Interferes with synthesis of 13 serotonin. 14 Q. Yes, from L-tryptophan. 15 A. Uh-huh. 16 Q. So in other words, the 17 tryptophan is there and the L-tryptophan is 18 there, but the body can't do anything with it 19 because of the inhibitor of the -- 20 A. Enzyme. 21 Q. Enzyme. So let's just -- so 22 if it can't synthesize the tryptophan or the 23 serotonin from the tryptophan, okay, is there a 24 correlation -- is extrapolated from that a Page 166 1 correlation between a decreased level of 2 tryptophan and serotonin dysfunction of some 3 sort, either the body's inability to produce it 4 or the quality of the serotonin or -- 5 MR. MYERS: You want to know if the 6 connection is the decreased -- a decrease in 7 tryptophan and thus in serotonin production? 8 MS. ZETTLER: Right. 9 A. Well, the inhibitor imposes 10 the dysfunction. 11 Q. Right. On the ability to 12 synthesize serotonin. 13 A. Yes. 14 Q. What I'm trying to get at is, 15 say you have somebody who for some reason is not 16 either getting tryptophan out of the food they 17 consume or is not consuming food that is a source 18 of tryptophan for some reason, is there, in your 19 opinion, a correlation between that lack of 20 tryptophan and either the level of serotonin in 21 the person's system or the serotonin's ability to 22 fire the neuron? 23 A. You want to extrapolate the 24 animal's experiment to human? Page 167 1 Q. Right. Well, you can do it 2 with animals, that's fine if you want to do it 3 with animals. 4 A. The experiment that I 5 described is, even though there's L-tryptophan 6 there, and when you inhibit the synthesis of the 7 enzyme, you prevent production of serotonin from 8 tryptophan, that way you may have abundant supply 9 of tryptophan. 10 Q. Right, but I'm asking -- if 11 you take out the L-tryptophan or tryptophan all 12 together, I mean will you extrapolate from that 13 study that you're talking about where the 14 synthesis of serotonin from tryptophan is 15 inhibited, would you extrapolate from that that 16 if the serotonin -- tryptophan is not present to 17 be synthesized into or to be changed into 18 serotonin, is there a correlation between a lower 19 level of serotonin and the lack of tryptophan? 20 MR. MYERS: You're saying no 21 tryptophan at all now? 22 MS. ZETTLER: Right, we can start with 23 no tryptophan at all. 24 A. If there's no tryptophan, then Page 168 1 there's no synthesis. 2 Q. Have you ever seen any studies 3 where a correlation has been done to see the 4 amount of tryptophan that's present, its 5 correlation with the amount of serotonin that has 6 been produced? 7 A. The amount of tryptophan 8 present correlate with the amount of serotonin 9 produced? 10 Q. Right. 11 A. Tryptophan present in where? 12 Q. Can you test for levels of 13 tryptophan in the blood? 14 A. The amount of tryptophan from 15 the blood to the brain is rather small. 16 Q. Well, you've got -- you 17 testified last time that your primary source or 18 people's primary source of tryptophan is in the 19 food that they consume, correct? 20 A. Yes. 21 Q. You can take a supplement, 22 there used to be L-tryptophan on the market that 23 you can take over-the-counter, amino acid 24 tablets, right? Page 169 1 A. Yes. 2 Q. But generally people get their 3 source of tryptophan or L-tryptophan from the 4 food they eat, like turkey, beef, protein, 5 various kinds of animal and plant proteins, 6 right, or combinations of proteins, things like 7 that? 8 A. Yes. 9 Q. Somehow it gets up to the 10 brain to be synthesized into serotonin, right? 11 A. Yes. 12 Q. And if that source of 13 tryptophan is taken away, then no tryptophan is 14 going to get to the brain to be changed into 15 serotonin. 16 A. From the tryptophan from the 17 food to the blood to the brain is more 18 complicated than just -- 19 Q. I understand that, I'm just 20 saying that is -- if you don't have any 21 tryptophan coming in, you're not -- no tryptophan 22 is going to get to your brain, right? 23 MR. MYERS: I just don't understand, 24 so I'm going to object to form. If no tryptophan -- Page 170 1 do you mean, in fact, no source of tryptophan? 2 Because he said food and protein was one source. 3 So is your question assuming that you don't get 4 any? 5 THE WITNESS: Yes, that's the main 6 source of tryptophan. 7 MR. MYERS: Right, but if it's the 8 main source and you cut it off, there will still 9 be some theoretically coming in. That's my 10 problem with your question. 11 MS. ZETTLER: From where, where would 12 other tryptophan come from if you don't have a 13 food source? 14 A. There are reservoirs in the 15 protein in the plasma. Tryptophan are bound to 16 the protein in the plasma, that's the reason why 17 I said feeding, you can supply tryptophan from 18 food stuff, but feeding tryptophan to the brain 19 is very complicated. 20 Q. But it's got to come from 21 somewhere to begin with, right? I mean say you 22 start out with somebody with no tryptophan 23 whatsoever from scratch, they're not going to 24 automatically have it stored, it's got to come Page 171 1 from the outside source like food to begin with, 2 right? 3 A. Right. 4 Q. And it's metabolized or 5 whatever and taken and stored in different areas, 6 and then used as the body requires it, correct? 7 A. Yes. 8 Q. The study you were talking 9 about earlier, was that the Charney study where 10 there was an inhibitor of the enzyme? 11 A. No. 12 Q. That's a different study? 13 A. The study that I talked about, 14 the inhibitor was done in animals. 15 Q. The Charney study is the 16 tryptophan depleted drink they were given? 17 A. Deficient. 18 Q. Deficient. Was that just a 19 drink that was deficient in tryptophan or was 20 that some sort of inhibitor that was being given 21 to the people who were taking the drink? 22 A. The drink containing fifteen 23 other amino acids. 24 Q. Okay. Page 172 1 A. And those amino acids compete. 2 Q. With the tryptophan? 3 A. With the tryptophan, to enter 4 the brain. That's the reason I said it's very 5 complicated. 6 Q. Okay. So the competing 7 between -- in a nutshell, the competing between 8 the other amino acids and the lower amount of 9 tryptophan prevents the tryptophan -- in other 10 words, makes it a deprived -- the tryptophan a 11 deprived drink, not as much tryptophan is going 12 to get where it needs to go? 13 A. Yes. 14 Q. Almost similar to the reuptake 15 inhibition of Fluoxetine and serotonin, they're 16 all fighting to go to the same area? 17 A. Okay, yes. 18 Q. Is that fair to say? 19 A. Yes. 20 Q. Do you know of any studies 21 where people who were depressed were given 22 tryptophan or L-tryptophan to study its effect on 23 their depression? 24 A. In the mid-'60s, such studies Page 173 1 were reported in mid-'60s. 2 Q. Do you know what the results 3 of those studies were? 4 A. Unfortunately those were not 5 double-blind studies, they were open studies. 6 Some reports said have antidepressive effects, 7 some said cannot be reproduced. So those studies 8 were very -- have yet to be confirmed with 9 double-blind, the type of the design. And in 10 general, the antidepressive effect of tryptophan 11 to this day still in debate. 12 Q. Okay. Are you aware that it's -- 13 you can't buy tryptophan or L-tryptophan 14 over-the-counter anywhere in the United States? 15 A. Beg your pardon? 16 Q. You can't go to like a health 17 food store and buy tryptophan or L-tryptophan 18 over-the-counter? 19 A. I don't know whether United 20 States, I think they become available again. 21 Q. Do you know when? 22 A. That, I don't remember. Maybe 23 last year, resumed supply and market. 24 Q. It was taken off the market Page 174 1 for awhile because there were problems with 2 L-tryptophan, or at least one manufacture of 3 L-tryptophan that was on the market, right? 4 A. Yes. 5 Q. Are you aware that there were 6 studies done out of Harvard that showed that 7 increased levels of L-tryptophan in massive 8 amounts -- amino acids, in general, not just 9 L-tryptophan, were correlated to brain damage, 10 neurological damage? 11 A. Would you repeat again, 12 please? 13 Q. Sure. Were you aware of 14 studies out of Harvard Medical School that 15 reported that there was a correlation between 16 mass amounts, I mean people megadosing themselves 17 on amino acids, not just tryptophan, but any 18 amino acid, and a neurological damage? 19 A. I'm not familiar with the 20 data. 21 Q. Would that be something you 22 would be interested from a tryptophan standpoint? 23 MR. MYERS: I object to the form only 24 because I don't really understand what you mean, Page 175 1 from a tryptophan standpoint? 2 Q. You've done research on 3 serotonin reuptake inhibitors, and integral in 4 that is the tryptophan, is it not? 5 A. Interesting in the animal 6 experimentation standpoint. In whether this 7 massive, like you suggest, did I have -- no, I'm 8 not interested in massive dosing of tryptophan in 9 animals. 10 Q. I'm talking about people. 11 A. I'm not qualified to do work 12 in humans. 13 MS. ZETTLER: Can we mark this as an 14 exhibit? 15 MR. MYERS: It depends on what you're 16 going to ask him about it since he drew on it in 17 response to a series of numerous questions and -- 18 MS. ZETTLER: I would just ask him if 19 this is what -- 20 Q. It's your drawing, you drew 21 that, right? 22 MR. MYERS: Well -- 23 MS. ZETTLER: And that it's basic, a 24 very basic layman's type description of -- Page 176 1 MR. SMITH: You don't have to get his 2 permission to mark it as an exhibit, just say 3 mark this as the next exhibit and pass it. 4 MS. ZETTLER: Mark this as the next 5 exhibit to the deposition, please. 6 (PLAINTIFFS' EXHIBIT NUMBER 6 7 WAS MARKED FOR IDENTIFICATION AND 8 RECEIVED IN EVIDENCE.) 9 Q. Doctor Wong, Exhibit Number 6 10 is the drawing that you did for me earlier, 11 correct? 12 A. Yes. 13 Q. Okay. And it's a basic 14 description of the serotonin producing cell and 15 the serotonin being placed into the synaptic 16 cleft, right? 17 A. Yes. 18 Q. And the receptor cell, 19 correct? 20 A. Yes. 21 Q. And the reuptake of serotonin, 22 correct? 23 A. Yes. 24 MS. ZETTLER: Let's take a break. Page 177 1 (A SHORT RECESS WAS TAKEN.) 2 Q. In a normal person with no 3 problem with their serotonin system, how much 4 serotonin is there in the synaptic cleft at any 5 given time? 6 A. I don't know. 7 Q. Does anybody know the answer 8 to that? 9 A. I don't know, I don't think -- 10 no, I don't know whether anybody knows it. 11 Q. How about in a normal rat, how 12 much serotonin is there in the synaptic cleft? 13 A. In the synaptic cleft, I don't 14 think anybody knows either. 15 Q. Is it difficult if not 16 impossible to measure that? 17 A. As I mentioned, technically, 18 the technical resolution hasn't reached that 19 degree of sophistication to be able to assess 20 concentration of neurotransmitters within the 21 synapse. 22 Q. Has anybody ever seen a 23 functioning synaptic cleft? 24 MR. MYERS: In? Page 178 1 Q. Start with animals. 2 A. Synaptic cleft? 3 Q. When I say functioning, I mean 4 in a live animal. 5 A. Functioning neuron, yes. 6 Q. Okay. 7 A. Whether it can monitor the 8 synaptic cleft, I don't think that has been 9 accomplished. 10 Q. So you have never personally 11 seen a serotonin synaptic cleft that was actually 12 functioning, you know, where the serotonin was 13 being dumped into the cleft and being used by the 14 receptor neuron? 15 A. Only able to see the 16 consequence of that event. But at that synaptic 17 cleft, that have yet to be accomplished. 18 Q. How about in humans, do you 19 know if anybody has been able to do that in 20 humans? 21 A. I don't know of anybody. 22 Q. Okay. We've been talking 23 about serotonin producing neurons and serotonin 24 receptor neurons, and things of that nature. Is Page 179 1 there any effect by any of the other 2 neurotransmitter on the serotonin producing 3 neuron? Like, in other words, does this neuron 4 that produces serotonin also produce Dopamine? 5 A. The same -- 6 Q. The same cell. 7 A. The same neuron produce 8 Dopamine? 9 Q. Right. 10 A. No. 11 Q. So while -- like there was a 12 serotonin producing neuron, there was also a 13 Dopamine producing neuron? 14 A. Yes. 15 Q. Is that true with receptors 16 also, serotonin receptors, but it's not affected 17 by Dopamine? 18 A. That's correct. 19 Q. So you have a whole other 20 group of cells that are there to produce and be 21 receptors for Dopamine? 22 A. Yes. 23 Q. Same thing with -- I always 24 screw this one up, the same thing with Page 180 1 Norepinephrine? 2 A. Norepinephrine. 3 Q. Same thing? 4 A. Yes. 5 Q. Cells that produce -- that 6 neurotransmitter and cells that react to that 7 neurotransmitter? 8 A. The receptors react to the 9 transmitters. 10 Q. Okay. And your research has 11 shown that Fluoxetine does not affect those other 12 cells, the Dopamine cells and the Norepinephrine 13 cells? 14 A. Fluoxetine does not inhibit 15 the uptake of Dopamine or Norepinephrine. 16 Q. In those cells that produce 17 it? 18 A. Yes. 19 Q. Does it have any effect 20 whatsoever on those cells? 21 A. Because it doesn't inhibit 22 uptake of Dopamine in this neuron, nor inhibit 23 the uptake of Norepinephrine, the Norepinephrine 24 contained neuron, so Fluoxetine have no direct Page 181 1 influence over those neurons. 2 Q. Does it have an indirect 3 influence? 4 A. Since serotonin innervate 5 other neurons as well -- 6 MR. MYERS: Did you say innervate? 7 A. Innervate, I-N-N-E-R-V-A-T-E. 8 Q. It innervates other neurons as 9 well as the serotonin neurons? 10 A. Yes. 11 Q. What other neurons? 12 A. Dopamine, Norepinephrine. 13 Q. When you say innervate, what 14 do you mean? 15 A. This could be a Dopamine 16 neuron, and this could be a Norepinephrine 17 neuron. 18 Q. And serotonin would affect 19 that neuron as well? 20 A. Yes. 21 Q. Is that true with Dopamine and 22 Norepinephrine, would it affect the serotonin 23 neurons as well? 24 A. Yes, they're all Page 182 1 interconnected. 2 Q. So this receptor will react 3 whether or not there is Dopamine in the synaptic 4 cleft or serotonin? 5 A. No, that synapse only contains 6 serotonin. 7 Q. So the synapse only -- let me 8 ask it this way and I think I might understand: 9 The receptor is the same across the board, what 10 differentiates what's in here is the cell that's 11 producing on the other side. 12 A. Yes, that cell facing a 13 serotonin neuron. 14 Q. So these neurons, the receptor 15 neurons, are not -- the only thing that makes 16 this receptor neuron that you drew in Exhibit 6 a 17 serotonin neuron is that serotonin is being 18 produced in this neuron synaptic cleft? 19 A. Serotonin produced in this 20 neuron. 21 Q. Right, I'm sorry, let me ask 22 it again. The only thing that makes the receptor 23 neuron that you drew in Exhibit 6 a serotonin 24 receptor neuron, is that across from it is a Page 183 1 serotonin producing neuron? 2 A. Yes. 3 Q. There is nothing different in 4 the structure of this neuron, the receptor 5 neurons for the serotonin-producing cell than a 6 Dopamine receptor or Norepinephrine receptor? 7 MR. HARRIS: Easy for you to say. 8 A. This neuron could have 9 Dopamine receptor in it, this neuron could have 10 Norepinephrine receptor. 11 Q. So it doesn't -- the structure 12 of this neuron is the same, there isn't anything 13 about this neuron that makes it only exclusive to 14 serotonin except for the fact that the cell 15 across from it is producing serotonin? 16 MR. MYERS: When you say this neuron, 17 you mean the receptor neuron? 18 MS. ZETTLER: Right. 19 A. Also when you say structure, 20 what do you expressly mean by structure? 21 Q. In other words, we know that 22 the producing cell here is a serotonin producing 23 cell. 24 A. Yes. Page 184 1 Q. The serotonin producing cell 2 produces only serotonin, it doesn't produce 3 Dopamine or any other neurotransmitter, right? 4 A. Not that I know of. 5 Q. All right. The receptor 6 cells, on the other hand, are all the same? 7 Forget about what neurotransmitter is -- 8 A. They could be all -- the 9 neuron could be neuron of all different 10 neurotransmitters. 11 Q. Okay. So let's say on Monday 12 this receptor is receiving serotonin, the next 13 day it could possibly be receiving Dopamine? 14 A. Oh, I see what you're driving 15 at. 16 Q. You see what I mean? 17 A. Well, if that neuron that 18 would persistently receiving this signal from 19 serotonin -- 20 Q. It would obviously receive 21 serotonin. But right next to it, theoretically, 22 could be a Dopamine receptor that is only 23 receiving -- 24 A. No, could be a Dopamine Page 185 1 neuron. 2 Q. That's what I meant, neuron. 3 That's only receiving -- is only being fired by 4 Dopamine, because the cell that's always across 5 from it is a Dopamine producing cell? 6 A. Whatever neurotransmitter that 7 may be, yes. 8 Q. Ultimately what I'm driving at 9 is these receptors are all the same? 10 MR. MYERS: What -- 11 Q. They're all the same. In 12 other words this receptor that is across from our -- 13 your drawing of the serotonin cell, okay, it can 14 have -- can be right next to another receptor 15 that's the same type of receptor except that it's 16 being triggered by Dopamine? 17 A. Whether the receptor is the 18 same receptor or not the same receptor, I don't 19 know how long that receptor exists in that cell. 20 Q. I think where I'm getting 21 confused is, before I thought that there was a 22 serotonin producing cell -- 23 A. Yes. 24 Q. -- that does nothing but Page 186 1 produces serotonin, correct? 2 A. Correct. 3 Q. And then there was a serotonin 4 receptor neuron that would only react -- it would 5 only react to serotonin? 6 A. No, no. 7 Q. Do you see where I'm driving 8 at now? 9 A. No. That neuron receives 10 signal from -- could be from many neurons, that 11 is serotonin signal being recognized by a 12 receptor on that neuron. 13 Q. So it's the receptor, it's not 14 the neuron itself? 15 A. That's right. 16 Q. So the neuron is the same, 17 it's the receptors that are different? 18 A. No. I need clarification, 19 what do you mean by neuron the same? 20 Q. Forget it, let me can ask it 21 this way: Can this receptor on this serotonin 22 neuron, okay, can it be -- 23 A. This is serotonin neuron. 24 Q. What is this, is it just a Page 187 1 neuron? 2 A. A postsynaptic receptor. 3 Q. A postsynaptic receptor 4 strictly for serotonin. 5 MR. MYERS: The receptor or the 6 neuron? 7 Q. Right, the receptor. 8 A. Yes. 9 Q. Because this neuron has 10 serotonin receptors, it is only going to be 11 affected by serotonin? 12 A. Yes. 13 Q. It's not going to be affected 14 by Dopamine or any other neurotransmitter? 15 A. Correct. 16 Q. So you could have all kinds of 17 Dopamine in here, it's not going to make a 18 difference? 19 A. No, no. This serotonin neuron 20 only allows serotonin passing, no Dopamine. 21 Q. Right, but I'm saying, say you 22 had the receptor with the serotonin -- the 23 serotonin receptor, okay? 24 A. Yes. Page 188 1 Q. And say somehow Dopamine got 2 in the synaptic cleft -- just bear with me for a 3 second -- it's not going to affect this receptor 4 because this receptor is a serotonin receptor. 5 A. Right, okay, I see what you 6 mean. That receptor only recognize serotonin. 7 Q. So Dopamine is not going to 8 affect that receptor, if you had it in the first 9 place. 10 A. The degree of specificity of 11 the receptor for a transmitter depend on 12 concentration of the neurotransmitter. In the 13 synapse, that probably -- that is correct to say 14 that that receptor would not accept Dopamine 15 because that receptor is specific for serotonin. 16 Q. Okay. 17 A. However, when you do 18 experiment in a test tube, you can increase 19 concentration of Dopamine, ten thousand time, for 20 instance, then you make that receptor to force 21 the receptor to take in Dopamine. 22 Q. To accept the Dopamine, to 23 respond to the Dopamine? 24 A. Yes. So -- but in reality, Page 189 1 what you said is correct. 2 Q. Okay. How is it then that 3 serotonin can affect other neurons other than 4 ones with serotonin receptor? 5 A. I beg your pardon, say it 6 again, please? 7 Q. Before you said -- I asked you 8 if it indirectly affected like the Dopamine and 9 Norepinephrine neurons? 10 A. Yes. 11 Q. And you said indirectly? 12 A. Yes. 13 Q. How does it affect it 14 indirectly then? 15 A. I was saying that Fluoxetine 16 only affect those neurons indirectly because of 17 the greater availability of serotonin. This 18 synapse could be synapsed to a Dopamine neuron, 19 this could be a Dopamine neuron, and this 20 receptor of serotonin can affect a Dopamine 21 neuron to release or not to release Dopamine, for 22 example. 23 Q. So you can have a Dopamine 24 neuron with a serotonin receptor, and the Page 190 1 serotonin tells it to start producing Dopamine? 2 A. Yes, it's more or less that 3 way. 4 Q. Does it work the other way 5 around, can a Dopamine neuron tell a serotonin 6 receptor to start producing serotonin? 7 A. The relationship between 8 serotonin and Dopamine, so far known to serotonin 9 affect Dopamine neuron, and have yet to 10 demonstrate the reverse. Yes, that's my correct 11 assessment. 12 Q. So so far nobody knows if the 13 reverse is true, that the Dopamine can cause a 14 serotonin nerve to start producing serotonin? 15 A. Correct. 16 Q. How does Fluoxetine affect the 17 Dopamine producing neuron, the same as it would 18 for a serotonin receptor? 19 A. Because of the greater 20 availability of serotonin, serotonin would 21 activate the receptor, which localized in the 22 Dopamine neuron. 23 Q. What you are concerned about 24 in your research was the effect of the serotonin Page 191 1 on the receptor, not necessarily the cell, the 2 neuron behind the receptor, what the neuron's 3 function was? 4 MR. MYERS: I object to the form only 5 because when you said what you were concerned 6 with, I don't -- I think I know what you mean, 7 but -- 8 Q. Let me try it again. Thank 9 you for being patient with me, Doctor, because 10 like I said I'm a rank layperson. 11 MR. SMITH: Quit marking on the 12 exhibit. 13 MS. ZETTLER: Oh, geez, I'm sorry. 14 MR. MYERS: We have some clean ones. 15 Q. Are you able to tell with any 16 given neuron what its function is, in other words 17 can you look at this neuron and tell it's a 18 Dopamine producing neuron? 19 A. Neurochemically one can 20 monitor the activity of a Dopamine neuron. 21 Q. Okay. And when you talked to 22 Paul the last time we were all together about the 23 different functions of serotonin, like regulating 24 blood pressure, and feelings of being full, and Page 192 1 mood, and things of that nature, are you talking 2 about serotonin's firing of neurons that are 3 related to those functions? 4 A. Yes, I think so. Let me 5 elaborate. This is not just one R, there is -- 6 there are about seventeen -- fifteen to seventeen 7 type of receptors of serotonin. 8 Q. On each neuron? 9 A. On various -- not necessarily 10 on each neuron, a neuron can have different type 11 of receptors. 12 Q. Seventeen? 13 A. Fifteen to seventeen. 14 Q. Fifteen to seventeen subtypes. 15 A. Yes, of serotonin receptors. 16 Q. What are the functions of 17 those subtypes? 18 A. We're just beginning to 19 understand the functional role of subtypes of 20 receptors of serotonin. 21 Q. Is there any understanding of 22 any particular subtype, what their function is? 23 A. For example, the receptor of 24 serotonin Two-C, considered to be involving Page 193 1 controlling of eating behavior. 2 Q. Now is the serotonin that 3 affects that receptor the serotonin Two-C subtype 4 receptor? 5 A. Yes. 6 Q. Is the serotonin any different 7 or is that the same? 8 A. Same serotonin. 9 Q. Same serotonin, again, it just 10 depends on what the receptor is? 11 A. Yes. 12 Q. Now is the receptor connected 13 to a particular neuron? 14 MR. MYERS: When you say the receptor, 15 do you mean -- 16 Q. The serotonin 2-C. 17 MR. MYERS: Okay. 18 A. What particular neuron, at 19 this point, is still unknown. 20 Q. Could a 2-C subtype neuron or 21 receptor be connected to a Dopamine producing 22 neuron? 23 A. There's no such evidence at 24 this point, 2-C receptor being present in the Page 194 1 Dopamine neuron. 2 Q. Which subtype of serotonin 3 receptor is present in the Dopamine neuron? 4 A. One of the possibility -- it 5 just remain a possibility is the serotonin 3 6 receptor. 7 Q. Possibly related to the 8 production of Dopamine? 9 A. For the control, release of 10 Dopamine. 11 Q. How about -- are there any, 12 like, 3-As or 3-Bs or anything like that? 13 A. There was some speculation of 14 having a 3-A, 3-B and 3-C. 15 Q. And those are all related to 16 the release of Dopamine? 17 A. Not so well delineated yet. 18 Q. Are there any other subtypes 19 that have -- whose purposes have been identified? 20 A. I'm sorry? 21 Q. Are there any other serotonin 22 receptor subtypes whose functions have been 23 identified? 24 A. The serotonin 2-A -- Page 195 1 Q. Okay. 2 A. -- have been known to mediate 3 the blood pressure, as well as eating, besides 4 2-C I mentioned. 5 Q. Okay. 6 A. It's been speculated serotonin 7 1-A receptor may mediate the antidepressive 8 effect of drugs. 9 Q. Any others? 10 A. Serotonin 1-D receptor have 11 been considered to be involved in the perception 12 of migraine headache. 13 Q. When you say perception, you 14 mean the feeling of pain? 15 A. Yes, migraine headache. 16 Q. Okay. 17 A. Serotonin three receptor, 18 again, might involve the emisis. 19 Q. Emisis, E-M-I-S-I-S? 20 A. Yes. 21 Q. How about 1-C? 22 A. 1-C -- 2-C used to be called 23 1-C. 24 Q. Okay. 2-C is now? Page 196 1 A. No. 2-C used to be known as 2 1-C, now the old 1-C now is known as 2-C. 3 Q. Okay. So used to be -- 4 MR. SMITH: That's because it was so 5 simple, you had to do something to complicate it. 6 Q. And what is that thought to 7 do, what is now known as 2-C, what is that 8 thought to do? 9 A. I mentioned to you that -- 10 Q. I'm sorry, controls eating 11 behavior? 12 A. Yes. 13 Q. How about 1-B? 14 A. 1-B is known to be present in 15 rodents only, and in human subject remain to be 16 identified. 17 Q. When you say that there's 18 seventeen -- fifteen to seventeen that have been 19 isolated or discovered at this point -- 20 A. Cloning, by cloning receptors. 21 Q. By cloning? 22 A. Cloning, yes, gene expression. 23 Q. These are serotonin receptor 24 subtypes that exist in all of our brains or are Page 197 1 these subtypes that have been manufactured 2 through cloning? 3 A. By cloning they have been 4 detected. 5 Q. They have been detected by 6 cloning? 7 A. Yes. 8 Q. But I have these subtypes and 9 you have these subtypes, and as far as we know, 10 we haven't been cloned, right? 11 A. Right. 12 MR. HARRIS: We don't know about you. 13 Q. Okay. When you say there are 14 fifteen to seventeen subtypes, are they -- does 15 that include 1-A, 1-B, 1-C or 1-D or is that one 16 through seventeen, and then you have A, B, C, D? 17 A. Let me list what would be 1-A, 18 1-B, 1-D, 1-E, 1-F, 2-A, 2-B and 2-C, 3, 3 could 19 be A, B, C. 20 Q. Could be? 21 A. Have been proposed to be. 22 Q. So that's where you get the 23 fifteen to seventeen? 24 A. I don't know if I have a final Page 198 1 count yet. 2 Q. Okay. So three -- wait to 3 make sure I get this right. Possibly -- 4 A. A, B, C. And then 4, 5-A and 5 5-B. 6 Q. Okay. 7 A. Six and 7. 8 Q. Okay. 9 A. Well, there's fourteen if you 10 don't count the possible 3A through C -- 11 A. Yes. 12 Q. -- and there's seventeen if 13 you count -- okay. How about 4, do you have any 14 idea what that's supposed to be? 15 A. Four so far have yet to be 16 demonstrated present in the brain, mostly in the 17 peripheral organs. 18 Q. Peripheral organs? 19 A. Yes. 20 Q. Such as? 21 A. The intestinal system. 22 Q. Okay. Any others? 23 A. I think that's the current 24 status of the knowledge. Page 199 1 Q. How about 5-A and 5-B? 2 A. 5-A and 5-B have been detected 3 in brain. 4 Q. Okay. Does anybody have any 5 idea what their function is? 6 A. It's so new, I don't think 7 that there's -- 8 Q. Any speculation? 9 A. No. 10 Q. How about 6? 11 A. Also just published in the 12 literature. 13 Q. How recently? 14 A. Last -- less than a year. 15 Q. Is that true with 7 also? 16 A. Yes, uh-huh. 17 Q. So 5-A, 5-B, 6 and 7 have just 18 been newly discovered? 19 A. Yes, all this is very new. 20 Q. How about 1-F? 21 A. 1-F, I don't know the 22 function. 23 Q. Nobody knows? 24 A. Nobody knows the function yet. Page 200 1 Q. How about 1-E? 2 A. Also. 3 Q. They just know they're there, 4 they don't know what they do yet? 5 A. That is right. 6 Q. How about -- why is 1-B 7 included if it's only found in rodents? 8 A. Perhaps -- this is still a 9 debate. 1-D, there's 1-D alpha and 1-D beta. 10 Q. And there's debate about this? 11 A. The amino acid sequence for 12 the 1-B in a rodent, such a receptor could not be 13 found in human brain. 14 Q. Neither the alpha or the beta? 15 A. Yes. So only the 1-D beta 16 seemed to have some homology close to the rodent 17 1-B. 18 Q. Okay. 19 A. So you may -- one may consider -- 20 this is a debate at this point. How much 21 homology that one can make, per se, that is being 22 1-B in human, is represented by 1-D alpha -- by 23 1-D beta. So that is unsettled at this point. 24 Q. Are these other receptors also Page 201 1 found in rodents or are these strictly human 2 receptors? 3 A. Beg your pardon? 4 Q. The other receptors, you know, 5 like 2-A, B and C, are those also found in 6 rodents or are they strictly human receptors? 7 A. Whether all of them have been 8 observed in rodents, I'm not certain, but most of 9 them have been found in rodents, except 1-D beta. 10 Q. Okay. 11 A. I'm sorry, even that had just 12 been changed. So in rodents, also have 1-D beta 13 now. So this area of research is going very 14 rapidly, and I'm sorry that I have to sit here. 15 Q. Probably changed already, 16 right, there's probably twenty now. Do rats have 17 1-A receptors? 18 A. Yes, it does. 19 Q. Does it have the same function 20 or does anybody know what function it has? 21 A. Since I don't know in animal 22 when it is depressed, I don't know whether 1-A, 23 if it has the same function in human as in rats. 24 Q. Okay. Can you tell from the Page 202 1 neuron what function it has just by looking at 2 the neuron itself? 3 A. When you talked about 4 function, there's different level of 5 characterization of function. 6 Q. Let me ask you this: Can you 7 tell by looking at the 1-A receptor that it's a 8 1-A receptor, just by looking at it, or is it 9 something that you have to do -- 10 A. If you analyze that receptor 11 of amino acid sequence, then you'll know that is 12 indeed 1-A, or if you study the signal 13 transduction process you're able to identify. 14 Q. Okay. Did you say the amino 15 acid what? 16 A. Amino acid sequence. Is the 17 amino acid sequence in the rodent 1-A the same as 18 the amino acid sequence in the human 1-A? 19 A. There are some subtle 20 differences. 21 Q. But you can differentiate from 22 the amino acid sequence a rodent 1-A as opposed 23 to a rodent 1-B? 24 A. Yes. Page 203 1 Q. Same thing with humans. 2 A. Yes. 3 Q. So theoretically, even though 4 we can't ask the rat how he's feeling on any 5 given day, the 1-A could still have something to 6 do with mood regulating in a rodent? 7 A. In a rodent, again, I don't 8 know what this mean of mood to the animal, how 9 would you assess mood in an animal. 10 Q. I'm saying theoretically, 11 since it's got the same amino acid sequence, that 12 even though you can't evaluate an animal's mood, 13 you can't ask a rat how it's feeling on any 14 particular day or tell whether or not it's 15 suffering from some form of depression, 16 theoretically, the neuron works the same as -- 17 A. You can check the biochemical 18 effect of 1-A in animals. 19 Q. And the biochemical effects of 20 1-A in a human being? 21 A. No, you cannot do that. 22 Q. Why? 23 A. That's inside the human brain. 24 Q. Can you do it on a postmortem Page 204 1 study? 2 A. Oh, I'm sorry, I meant a 3 living brain. 4 Q. But you could do it on a 5 postmortem study? 6 A. Yes. 7 Q. Can you do it on a postmortem 8 study on a rat? 9 A. Yes. 10 Q. Okay. To your knowledge, has 11 anybody ever done that on a postmortem study on a 12 human? 13 A. Certain 1-A, yes. Some in 14 Japan, some scientist in Japan, a patient with 15 schizophrenia in subtype, in subgroup, a 16 schizophrenia patient, they did measure the 1-A 17 receptor in those postmortem tissue. 18 Q. What were the results of that 19 study? 20 A. Only in a very selective 21 cortical area, they observed a higher density of 22 the serotonin 1-A receptor. 23 Q. How did that compare to the 24 normal brain? Page 205 1 A. That was compared to normal 2 brain. 3 Q. So it's a higher density in 4 that one cortical area than the normal brain? 5 A. Yes. 6 Q. Did they extrapolate anything 7 with regards to schizophrenia from that finding? 8 A. They didn't in the experiment. 9 Q. Was it just one patient? 10 A. A small number of individuals 11 postmortem x-ray studies. 12 Q. Let's get back to your down 13 regulation study, the first one. What were the 14 results of that study? 15 A. You mean the study I did? 16 Q. Yes, your study. 17 A. In '82, I believe it was -- I 18 reported that repeat administration of Fluoxetine 19 up to twenty-one days, we observed a down 20 regulation of serotonin 1 receptor. 21 Q. Is that different than a 22 serotonin 1-A? 23 A. At that time, 1-A wasn't 24 known. Page 206 1 Q. Was unknown, okay. 2 A. A subtype receptor known at 3 the time was only 1 family and 2 family were 4 known, and I only looked at the serotonin 1 5 receptor. 6 Q. So you didn't even look at 2, 7 you just looked at 1? 8 A. I did look at serotonin 2 9 receptor, had no effect. 10 Q. No effect on serotonin 2, but 11 you did have a down regulation of serotonin 1. 12 A. Yes. 13 Q. Serotonin 1 at that time, what 14 was that receptor's function thought to be? 15 A. That would be the function of 16 the serotonergic neuron. 17 Q. Producing serotonin? 18 A. In the cortical area, that 19 would be the postsynaptic receptor. 20 Q. So it wasn't the neuron that 21 produced or contained serotonin, it was the 22 neuron on the other side of the synapse? 23 A. Receiving. 24 Q. What was that function of that Page 207 1 neuron thought to be back then? 2 A. I don't know particular that 3 function, that is -- like you said, it's grind 4 and bind type of experiment, we did not identify 5 what the function of that particular receptor 6 which was down regulated. 7 Q. Those receptors that you knew 8 back in '82 as 1, serotonin 1 receptors? 9 A. Yes. 10 Q. Were those all broken off 11 eventually into different A, B, C, D categories? 12 A. Yes. 13 Q. And across the board, were 14 they all affected the same as far as down 15 regulation? 16 A. So far there's no -- have yet 17 to study, do those studies, and the laboratory 18 have done those studies, one study was the 19 serotonin 1-A receptor being studied. 20 Q. I'm talking just that first 21 study. 22 A. Yes. 23 Q. Where you looked -- you said 24 that you had found down regulation of the Page 208 1 serotonin 1 receptor. 2 A. Yes. 3 Q. Correct? 4 A. Yes. 5 Q. Now we know -- back then you 6 didn't, but now you know that there are subtypes 7 within the subtypes, right, 1-A, 1-B, 1-C, or 2-C 8 now, D. Were they all affected the same as far 9 as down regulation? 10 A. That's what I'm trying to say, 11 there's no such study being done at this point. 12 Q. I'm saying in your study, did 13 you see a difference in how much -- 14 A. I didn't know that those 15 receptors existed. 16 Q. You thought it was all the 17 same receptor at that time? 18 A. Yes, the one family receptor. 19 Q. Were all the one family 20 receptors that you studied affected the same as 21 far as the amount of down regulation that 22 occurred? 23 MR. MYERS: I object to the form. I 24 think he answered that, he said he didn't know Page 209 1 about the other ones at the time. So if he 2 didn't know at the time, how could he know that? 3 MS. ZETTLER: See, that's what -- 4 MR. MYERS: I understand what you're 5 trying to ask him, but it didn't come out that 6 way. 7 Q. At the time you were only 8 looking at two different receptors? 9 A. Yes. 10 Q. And you said the one family 11 earlier, right? 12 A. Yes. 13 Q. Were you looking at the one 14 family back then or were you just looking at 1? 15 A. One, because there's only one 16 receptor at that time. There were two receptors 17 known at that time, serotonin 1, serotonin 2 18 receptors. 19 Q. The serotonin 1 receptor that 20 you saw in 1982 -- 21 A. Yes. 22 Q. -- what is that named now? 23 A. Now have been broken down into 24 subset, subtype. Page 210 1 Q. So really, you were looking 2 at, as it turns out, more than one receptor? 3 A. Could be. 4 Q. Okay. Go ahead. 5 A. Yes, you're correct, it's in 6 the cortical area is what I'm saying. 7 Q. In the cortical area. What 8 you thought was the 1 receptor or -- did you know 9 it was the 1 family back then? 10 A. No. 11 Q. You thought it was just one? 12 A. Just one. 13 Q. Did you look at more than one 14 subtype 1 neuron or receptor, I mean, in other 15 words, you didn't just isolate one single subtype 16 1 receptor and look at that one receptor, did you 17 look at -- 18 A. I should be more specific. I 19 was doing the binding of radioactive serotonin to 20 that receptor. 21 Q. So the -- so it may have been 22 to what is now the family of one receptors? 23 A. Yes. 24 Q. You don't know that for sure, Page 211 1 though, or do you know that now? 2 A. Because of the condition that 3 binding was conducted, and I can only say that 4 that binding occurred to a member of the 1 5 family. 6 Q. Okay. 7 A. A member or members of. 8 Q. You don't know for sure, 9 though? 10 A. Yes. 11 Q. So it is possible that it was 12 binding to all, what is it, three members now or 13 four members now of the 1 family? 14 A. If those receptors present in 15 the frontal cortical area. 16 Q. But you were just looking at 17 one down regulation effect, in other words you 18 didn't see that -- I'm going to use another 19 layman's example -- you didn't see that some of 20 the 1's down regulated fifty percent and some 21 down regulated twenty-five percent, you just saw 22 1 down regulation effect across the board? 23 A. Yes. 24 Q. Okay. And there was no effect Page 212 1 on 2? 2 A. Yes. 3 Q. Yes, there was no or -- 4 A. No effect on 2. 5 Q. This was after you had kept 6 the rats on the Fluoxetine for twenty-one days? 7 A. Yes. 8 Q. Did you start any -- or did 9 you do it in increments going up to twenty-one or 10 did you put them all on twenty-one across the 11 board? 12 A. I did reverse. After seeing 13 the effect on twenty-one days on down regulation, 14 then I treated animal in shorter duration. 15 Q. What is the shortest duration 16 you treated an animal on? 17 A. Two days. 18 Q. Did you see down regulation in 19 those animals? 20 A. I believe two days, I didn't 21 see down regulation. 22 Q. You did not? 23 A. I did not see down regulation. 24 Either the third day or the fourth day beginning Page 213 1 to see detectable down regulation, that's what I 2 recalled. 3 Q. So you put some rats on for 4 two days. 5 A. Yes. 6 Q. And you don't recall seeing 7 any down regulation on the rats who were on it 8 for two days? 9 A. Yes. 10 Q. Did you add a day, did you do 11 the next group at three and the next group at 12 four or did you add a couple of days at a time? 13 A. Yes. 14 Q. Couple a days at a time? 15 A. Yes. 16 Q. So like say the next group was 17 on it for four days? 18 A. Either third day or fourth 19 day, and it just arbitrary set of intervals. 20 Q. Do you remember what 21 intervals? 22 A. One week later, and then two 23 weeks, and then twenty-one days or three weeks. 24 Q. All of those rats that you Page 214 1 studied on down regulation over four days, did 2 you see down regulation in the 1 subgroup, 3 subtype? 4 A. Yes, detectable down 5 regulation of serotonin 1 receptor. 6 Q. Was the level of down 7 regulation, did it become greater as the time 8 went on or was it something that was the same 9 across the board? 10 A. There is a higher down 11 regulation in longer time of treatment. 12 Q. So it correlated to how long 13 you had the rats on the Fluoxetine? 14 A. Yes. 15 Q. Okay. Was there -- 16 A. I believe that there's no 17 difference between two weeks or three weeks, if I 18 remember correctly. 19 Q. So once you got to two weeks, 20 there wasn't a difference between the amount of 21 down regulation between that group of rats and 22 the group of rats who were on it for twenty-one 23 days? 24 A. Yes. Page 215 1 Q. How about the rats who were on 2 it for twenty-five days? 3 MR. MYERS: I thought he said it was a 4 twenty-one day study. 5 A. Subsequently, the second paper -- 6 MR. MYERS: Twenty-five was a 7 different study? 8 THE WITNESS: Yes, different paper. 9 Q. So the ones -- after you did 10 the twenty-one, the initial study on twenty-one 11 days, and then you went back and started raising 12 the -- or extending the time incrementally, that 13 was all part of one study? 14 A. No, it is a separate, three 15 years later. I was trying to do autoreceptors -- 16 receptors autoneurotransmitters, receptors of 17 Norepinephrine. It was a preexamining theory 18 that down regulation of the beta adrenergic 19 receptor, explained for the efficacy of the 20 tricyclic antidepressant. 21 Q. Okay. 22 A. And, so, my interest was would 23 Fluoxetine down regulate the beta adrenergic 24 receptor. Page 216 1 Q. Did it? 2 A. It doesn't. 3 Q. Does it down regulate any 4 other receptor besides the Serotonin 1, at least 5 at that point? 6 A. No. 7 Q. Is it related to the adrenal? 8 A. Yes. 9 Q. Did you try to determine 10 whether or not any other antidepressants caused 11 down regulation of any receptors? 12 MR. MYERS: When? 13 Q. During this time period when 14 you were studying down regulation of Fluoxetine. 15 A. I did with desipramine. 16 Q. Was that a similar study? 17 A. To ascertain what was 18 published in the literature, if that down 19 regulated beta adrenergic receptor. 20 Q. Did it? 21 A. It did. 22 Q. Did it have any effect on the 23 serotonergic receptor? 24 A. I didn't do that experiment. Page 217 1 Q. Okay. Is Desipramine thought 2 to have some properties of inhibiting reuptake of 3 serotonin? 4 A. Desipramine is very weak 5 ability to inhibit uptake of serotonin. 6 Q. Is Desipramine Desyrel, is 7 that the same drug? 8 A. No. 9 MR. MYERS: I don't think so. 10 A. Desyrel is Trazodone. 11 Q. How about Trazodone, does that 12 have any ability to inhibit the reuptake of 13 serotonin? 14 A. Initially the Italian 15 investigators report Trazodone inhibit uptake of 16 serotonin. I believe they measure uptake of 17 serotonin in human platelet, and call Trazodone 18 as an inhibitor for uptake of serotonin. 19 Q. Last time when you were 20 talking to Paul, did you say there was a 21 correlation between the inhibition of the uptake 22 of serotonin in platelets to the inhibition of 23 uptake of serotonin in neurons, is there a 24 correlation? Page 218 1 A. No. I don't believe that I 2 made that statement. 3 Q. Okay, that's what I'm trying 4 to clarify. Did you find that serotonin did 5 inhibit the reuptake -- I'm sorry, did you find 6 that Fluoxetine did inhibit the reuptake of 7 serotonin in platelets? 8 MR. MYERS: At the same time he's 9 doing these animal studies? 10 MS. ZETTLER: Anytime. 11 A. Fluoxetine does inhibit uptake 12 of serotonin in platelets. 13 Q. To the same extent that it 14 does in neurons in the brain? 15 A. When you say that to the same 16 extent, do you -- 17 Q. Well, in rats you said you'd 18 gotten in living organisms as much as eighty 19 percent inhibition, right? 20 A. Yes. 21 Q. Is that true of platelets, 22 have you seen that as much in platelets? 23 A. Ex vivo, it's comparable. 24 Q. So we've got two down Page 219 1 regulation studies that you did with Fluoxetine, 2 one was the twenty-one day study that you found 3 some down regulation, correct? 4 A. (Witness moves head up and 5 down.). 6 Q. You have to say yes or no. 7 A. Yes. 8 Q. I know it's getting late, I'm 9 sorry. And the second one is the incremental 10 study that you did as a follow-up? 11 A. The incremental, it's the same 12 continuous study. 13 Q. But it was done a period 14 afterwards, it wasn't -- 15 A. The twenty-five day was done 16 after. 17 Q. So -- okay. So you considered 18 the first study, the twenty-one days and the 19 incremental following after the twenty-one days, 20 right? 21 A. Yes, the one set of 22 experiments. 23 Q. Okay. And then another one we 24 know about is the one we had him on for Page 220 1 twenty-five days? 2 A. Yes. 3 Q. Is that the next one that you 4 did? 5 A. The subsequent attempt to find 6 out if Fluoxetine down regulate, not only 5HT-1 7 receptor, if it down regulate the beta adrenergic 8 receptor. 9 Q. Did you find that it down 10 regulated the beta adrenergic receptor? 11 A. It doesn't down regulate the 12 beta adrenergic receptor. 13 Q. In the twenty-five day study 14 did you still find evidence of the down 15 regulation of the serotonin receptor? 16 A. Yes. 17 Q. So that's two separate 18 studies, right? You said earlier that you did 19 six down regulation studies. 20 A. No, those are total. The six 21 different experiments -- 22 Q. The incremental experiments, 23 you considered each of those individual 24 experiments? Page 221 1 A. Yes. 2 Q. So that's all the studies 3 you've done on down regulation? 4 A. That's an approximate number 5 that I can recollect. That's the best that I can -- 6 I first do a three week experiment, then I do a 7 two week experiment, and then do a one week 8 experiment, and then do a four day experiment, 9 and then two day experiment, and then I also did 10 a twenty-four hour experiment. And then I 11 stopped doing it, and then three weeks later and 12 do the twenty-five day study. 13 Q. So let's consider that two 14 separate studies, just for purposes of clarity. 15 The first one where you did the twenty-one day, 16 and then the follow-up incremental study, right, 17 and the second one the twenty-five day study that 18 you did a couple of years later to look at beta 19 adrenergic down regulation as well as serotonin 20 receptor down regulation? 21 A. Yes. And also, I did also 22 alpha adrenergic receptor, and alpha-1 and 23 alpha-2 receptor. 24 Q. Did you find any down Page 222 1 regulation in either of those? 2 A. No. 3 Q. Is that the same twenty-five 4 day study? 5 A. Yes. And then also do a 6 histamine receptor. 7 Q. Any down regulation? 8 A. No effect. And also looked at 9 the gamma receptor. 10 Q. The which receptor? 11 A. The gamma-aminobutyric acid. 12 Q. Okay. 13 A. That had no effect. 14 Q. Is that GABA? 15 A. GABA. And histamine receptor. 16 Q. Okay. And no effect on that 17 one either, right? 18 A. Right. 19 Q. Have you done any other down 20 regulation studies besides those two major ones? 21 A. Yes. 22 Q. Okay. What other ones, do 23 they have to do with Fluoxetine? 24 A. No. Page 223 1 Q. Any other serotonin reuptake 2 inhibitors? 3 A. Yes. 4 Q. Without telling me what -- 5 MR. MYERS: Don't tell her what the 6 compound is, see what the question is. 7 Q. Did you find any down 8 regulation with that other inhibitor? 9 A. The newer compound had a 10 little different characteristic from just inhibit 11 uptake of serotonin. So it's not the same kind 12 of molecule and mechanism. 13 Q. Is it meant to affect another 14 neurotransmitter as well as serotonin? 15 A. Yes. 16 Q. What was the dominant 17 property, was it more predominantly a serotonin 18 reuptake inhibitor? 19 MR. MYERS: Doctor Wong, I'm going to 20 at this point instruct you, don't answer that 21 question because that may end up in disclosing 22 what the compound is. So I'm going to direct him 23 not to answer that. It's not Fluoxetine, he's 24 already told you it's a different molecule, with Page 224 1 different properties, and I'm instructing him not 2 to answer that because I think he's told you. 3 Q. Is the serotonin reuptake 4 inhibitor portion of the compound similar to 5 Fluoxetine? 6 MR. MYERS: He can answer that. You 7 can tell her that. 8 A. It's difficult to dissect 9 which portion. 10 Q. In other words did you start 11 with, say, Fluoxetine as a basis and then add the 12 portion of the compound -- 13 A. It's different structure. 14 Q. You said -- 15 A. It's a different structure. 16 Q. It is a different structure, 17 okay. Did the down regulation studies that you 18 performed on that compound, did you uncover any 19 down regulation of receptors? 20 A. Beg your pardon? 21 Q. On the down regulation studies 22 of that compound that you did, did you find any 23 down regulation of receptors? 24 A. It down regulate beta Page 225 1 adrenergic receptors. 2 Q. Did it down regulate the 3 serotonin receptors, any of the serotonin 4 receptors? 5 A. It down regulated serotonin-2 6 receptor. 7 Q. I may have asked you this 8 earlier, and if I did I apologize. But on your 9 studies of like Desipramine and the other 10 compounds that you studied for the adrenergic 11 alpha and beta receptors -- 12 A. Yes. 13 Q. -- did any of those compounds 14 have a down regulation effect on the serotonin 15 receptors? 16 A. Uh -- 17 Q. Like the -- 18 A. In literatures have been 19 reported those compounds. 20 Q. How about in your studies, 21 though? 22 A. I didn't look. 23 Q. You didn't look to see if it 24 had any down regulating effect? Page 226 1 A. I take it back, I did look at 2 the Serotonin 1-A receptor, it have no effect. 3 Q. That's Desipramine? 4 A. Yes. And serotonin 2 5 receptor, it down regulated. 6 Q. It did down regulate it? 7 A. Yes, as reported in the 8 literature. 9 Q. So you found similar results 10 as the literature reported? 11 A. Yes. 12 Q. Have you done any down 13 regulation tests strictly with Fluoxetine since 14 all of these other receptors have been 15 identified? 16 MR. MYERS: Up to seventeen? 17 MS. ZETTLER: Right. 18 MR. MYERS: Up to seventeen. 19 A. I told you that I did the 20 serotonin 1 receptor, serotonin 2 receptor. I 21 think also, most recently, I did a 1-A receptor. 22 Q. With Fluoxetine? 23 A. Yes. And did not see down 24 regulation effect on the 1-A receptor. Page 227 1 Q. For how long did you have the 2 rats on the Fluoxetine? 3 A. Ten days, I believe. 4 Q. Was that study published? 5 A. I think -- I don't believe so. 6 Q. Did you do all of these down 7 regulation studies on your own or did you do it 8 at the request of somebody else at Lilly? 9 A. Pretty much on my own. 10 Q. When you say pretty much on 11 your own, what do you mean? 12 A. Yes, on my own. 13 Q. Did you discuss your findings 14 with anybody else at Lilly? 15 MR. MYERS: Which studies? 16 MS. ZETTLER: The down regulation 17 studies with Fluoxetine. 18 A. That have been as a 19 consequence of reading a paper of somebody else 20 that had done that, and I tried to reproduce the 21 data. 22 Q. With Fluoxetine? 23 A. With Fluoxetine. 24 Q. Whose paper? Page 228 1 A. That was done in McGill 2 University, Montreal. 3 Q. McGill, M-C-G-I-L-L? 4 A. Uh-huh. 5 Q. Do you remember when that 6 study was published? 7 A. 1990 -- either '91 or '92. 8 Q. Do you remember the name of 9 the doctor who authored that? 10 A. The first author, I believe, 11 is a Wellner. 12 Q. You have to spell that, sorry. 13 A. W-E-L-L-N-E-R. 14 Q. Wellner. Anybody else that 15 you recall? 16 A. The last name, I only remember 17 the last name, perhaps it's Blair, but Wellner is 18 the first name. 19 Q. Spell the last name. 20 A. B-L-A-I-R. 21 Q. Blair? 22 A. Uh-huh. 23 Q. The first down regulation 24 study that you did, the twenty-one days with the Page 229 1 incremental follow-up, where was that published? 2 A. I believe that was published 3 in Life Science. 4 Q. Do you remember what year? 5 A. Maybe '82. 6 Q. And how about the second study 7 that you did, twenty-five day study? 8 A. That was published in '85. 9 Q. In Life Science? 10 A. In Journal of 11 Neurotransmission. 12 Q. There's a whole journal on 13 this? 14 A. Beg your pardon? 15 Q. You have a whole journal on 16 this? 17 MR. MYERS: You don't get it, don't 18 take it? 19 MS. ZETTLER: No, not yet, I may now. 20 MR. MYERS: Paul does. 21 Q. (BY MS. ZETTLER) Is down 22 regulation the same as decline in serotonin 23 turnover? 24 A. No. Page 230 1 Q. What is serotonin turnover? 2 A. Turnover means the release and 3 synthesis or the rate of replenishment. 4 Q. Okay. The rate of 5 replenishment of serotonin? 6 A. The rate of synthesis, the 7 composite picture of this steady state in which 8 the rate of release and synthesis was being 9 described, that's the turnover. 10 Q. The steady state at which -- 11 A. Let me illustrate. 12 Q. Okay. 13 A. Like a city like Indianapolis, 14 you have so many -- the total number of 15 automobile is constant. 16 Q. Okay. 17 A. Then the out-going automobile 18 is the same as the in-coming automobile, so make 19 that the steady state condition. 20 A. So that process of the 21 simultaneous process is being described as 22 turnover. 23 Q. So the serotonin producing 24 neuron is producing as much serotonin as being Page 231 1 released at the other end? 2 A. Yes. 3 Q. And when you say -- when you 4 talk about decline in the serotonin turnover, are 5 you talking about the decrease in the rate of 6 serotonin that's being produced or the decrease 7 that's being released? 8 A. When one described a decline 9 in turnover of serotonin, suggests that that is 10 the rate of release and the rate of synthesis 11 being attenuated while the steady state being 12 maintained. 13 Q. So the steady state is 14 maintained, but the rate it's being synthesized 15 and released is declining? 16 A. Yes. 17 (PLAINTIFFS' EXHIBIT NO. 7 WAS 18 MARKED FOR IDENTIFICATION AND 19 RECEIVED IN EVIDENCE.). 20 Q. Before you take a look at 21 that, Doctor, how do you know that the amount of 22 serotonin stays the same even though the 23 synthesis and the release is declining? 24 A. One can measure the Page 232 1 concentration, the level of serotonin in the 2 tissue. 3 Q. When you say in the tissue, 4 you mean in the receptors? 5 A. No, in the brain tissue. 6 Q. So you're looking at it not 7 from as the amount of serotonin that's being 8 placed into the synaptic cleft, you're looking at 9 it as the total amount of serotonin that is in 10 the brain tissue itself? 11 A. Yes. 12 Q. And how do you know that the 13 rate that it's being synthesized and released is 14 decreased? 15 A. One way to do it is to measure 16 the amount of metabolite of serotonin produced, 17 and then also the formation of 18 5-hydroxytryptophan. 19 Q. Which is the? 20 A. Precursor for the synthesis of 21 serotonin. So technically you can monitor the 22 increment in time with the change in 23 concentration of 5-hydroxytryptophan or the 24 decline, the rate of decrease or change of Page 233 1 5-hydroxyindoleacetic acid. 2 Q. And that's the enzyme? 3 A. No, that is the metabolite of 4 serotonin. 5 Q. That's the metabolite, okay. 6 5-hydroxytryptophan -- 7 A. Yes. 8 Q. Is that the metabolite? 9 A. Precursor. 10 Q. Precursor for? 11 A. Serotonin synthesis. 12 Q. Where is that in the structure 13 we talked about earlier, the tryptophan? 14 A. Tryptophan, and would be 15 converted to 5-hydroxytryptophan. 16 Q. Which is then converted to 17 serotonin? 18 A. Yes. 19 Q. So it's the thing in the 20 middle? 21 A. Yes. 22 Q. When you talk about the 23 synthesis and the release of serotonin, you're 24 talking about the synthesis and the release of Page 234 1 serotonin into the synaptic cleft, correct, or 2 out of the cell? 3 A. In the total brain tissue. 4 Q. But this is -- when you talk 5 about a release, you're talking about a release 6 by the cell, it's been produced and it's being 7 released by the cell? 8 A. Yes. 9 Q. How do you know that the 10 decrease in the metabolite is related to a 11 decrease in the synthesis and release of the 12 serotonin if the amount of serotonin stays the 13 same within the brain tissue? 14 A. You can measure the level of 15 serotonin in tissue unchanged, all the serotonin 16 is within the serotonin neuron. 17 Q. Okay. 18 A. So whatever you measure in the 19 brain tissue is inside and it is unchanged. 20 Q. Right, but what I'm asking is 21 if less serotonin is being metabolized, but the 22 amount of serotonin in the brain tissue is 23 staying the same, how does that indicate that 24 there's a decrease in the synthesis and release Page 235 1 of serotonin by the cell? 2 A. Under what condition is being 3 decreased? 4 Q. Under which condition, I'm 5 sorry? 6 A. Under what condition, the 7 serotonin -- 8 Q. In the turnover, you say -- 9 why don't you take a look at Exhibit 7. 10 A. Oh, that's Doctor Fuller's. 11 Q. Go ahead and read it. 12 MR. MYERS: Off the record. 13 (DISCUSSION OFF THE RECORD.) 14 Q. The last full sentence of the 15 summary says the decline in serotonin turnover 16 presumably is a compensatory mechanism occurring 17 when receptor sites are overstimulated due to 18 blockade of the reuptake, paren, inactivation, 19 close paren, of serotonin at the nerve synapse. 20 Correct? 21 A. Correct. 22 Q. Did you see such a decline of 23 serotonin turnover in your testing of rats? 24 A. This is Doctor Fuller's Page 236 1 experiment. 2 Q. Okay. But, I mean, in your 3 testing did you see evidence of this compensatory 4 mechanism that he talks about? 5 MR. MYERS: Before he answers, let me 6 object to the form only to the extent I don't 7 know that we've established what -- and I don't 8 know, that what Doctor Fuller is reporting on 9 here is the same kind of study he did, so -- 10 MS. ZETTLER: I'm not asking him that 11 I'm asking him in his -- 12 Q. In your studies that you 13 performed on rats, did you see a similar type -- 14 A. I didn't do the turnover 15 studies, Doctor Fuller does, so I don't know. 16 Q. You studied receptors, did you 17 not? 18 A. I did receptors, yes. 19 Q. Did you see any evidence of a 20 compensatory mechanism occurring in the receptors 21 in any of your studies? 22 A. The down regulation of 23 receptors is also an expression of compensatory 24 mechanism. Page 237 1 Q. Okay. Would your findings in 2 the down regulation of receptors coincide with 3 what Doctor Fuller talks about here? 4 A. Doctor Fuller's study here is -- 5 was mainly conducted to acute effect. 6 Q. Acute effect? 7 A. Yes. 8 Q. So immediately upon giving the 9 dosage of Fluoxetine, correct? 10 A. Yes. 11 Q. Did you see a similar 12 compensatory mechanism occurring in your studies 13 on down regulation over longer periods of time? 14 A. I did mention to you earlier 15 that after repeat administration of Fluoxetine, 16 lead to the down regulation of serotonin 1 17 receptor. 18 Q. Does down regulation have 19 anything to do with serotonin turnover? 20 A. I think that the turnover have 21 to do with the presynaptic neuron, whereas the 22 down regulation was the postsynaptic neuron. So 23 Doctor Fuller's study is different from my study 24 of the -- my study being at the receptor of the Page 238 1 postsynaptic neuron. 2 MS. ZETTLER: Let's take a break. 3 (A SHORT RECESS WAS TAKEN.) 4 Q. Are you familiar with a Doctor 5 Shulman, S-H-U-L-M-A-N? 6 A. Was that -- he's a former 7 Lilly associate colleague. 8 Q. I believe so. 9 A. Yes, I know of him. 10 Q. Okay. Are you aware that at 11 one point in time the project to develop 12 Fluoxetine as an antidepressant was scrapped by 13 Lilly? 14 MR. MYERS: I object to the form, I 15 don't know that that terminology is precise. I 16 object to the form. Do you know that? 17 A. Never thought being scrapped. 18 Q. Do you know that -- are you 19 aware that for a period of time the development 20 and testing of Fluoxetine was stopped, and was 21 resurrected by Doctor Slater? 22 A. It's not that there's no 23 interest in the compound, it's just Doctor 24 Shulman left and someone to pick it up, that's Page 239 1 all. 2 Q. So Doctor Shulman never 3 stopped the development of Fluoxetine as an 4 antidepressant? 5 A. No, I'm not aware that was the 6 situation. 7 Q. Doctor Slater testified to 8 that during his deposition. 9 MR. MYERS: Is that a question or are 10 you telling him that, do you want to know if he 11 knows that? 12 MS. ZETTLER: Right. 13 A. That's news to me. 14 Q. Have you studied amphetamines 15 at all, the effect of amphetamines on 16 neurotransmission? 17 A. I only use amphetamines in a 18 test tube to study effect of amphetamines on 19 uptake of serotonin and uptake of Norepinephrine. 20 Q. Did you see any effects on the 21 uptake of serotonin in the amphetamines in a test 22 tube? 23 A. You have to use very high 24 concentration of amphetamines to have an effect Page 240 1 on the serotonin uptake in synaptosomes. 2 Q. How about cocaine, have you 3 ever tested cocaine and its effects on 4 neurotransmission? 5 A. I didn't look at 6 neurotransmission again. 7 Q. Did you test it in a test 8 tube? 9 A. Yes, on uptake of serotonin, 10 yes. 11 Q. What was its effect on the 12 uptake of serotonin? 13 A. Again, it's very weak in the 14 uptake of serotonin, in my hand. 15 Q. In your hand? 16 A. In my laboratory. 17 Q. Did you ever test it on rats? 18 A. No. 19 Q. Why not? 20 A. That is a different area of 21 research to study cocaine on rats. 22 Q. How about methadone, did you 23 study that? 24 A. I did study the effect of Page 241 1 methadone in reuptake of serotonin in preparation 2 of synaptosomes. 3 Q. In a test tube? 4 A. In a test tube, yes. And also 5 by tests ex vivo for inhibition of uptake of 6 serotonin in down regulation, and find no effect. 7 Q. No effect on the uptake, 8 inhibition of the uptake. Did you ever test 9 Fluoxetine in combination with any other compound 10 on rats? 11 A. I don't recall any combination 12 that I have conducted with Fluoxetine, no, I 13 don't. I didn't combine Fluoxetine with any 14 other drug in my test. 15 Q. Do you know of any studies at 16 Lilly that were done on animals combining -- 17 A. Wait a minute, a correction. 18 I did use Fluoxetine treatment, and then treated 19 animal with para-chloroamphetamine. 20 Q. What is a 21 para-chloroamphetamine? 22 A. Para-chloroamphetamine would 23 gain entrance into the -- which is halogenated 24 amphetamine. H-A-L-O-G-E-N-A-T-E-D. Page 242 1 Q. What does that mean? 2 A. It means adding a chloro to 3 the molecule of amphetamine. 4 Q. What's the purpose of doing 5 that? 6 A. To make the molecule have a 7 different specificity compared to amphetamine, it 8 would be a different drug. 9 Q. Is the chloral additive meant 10 as a sedative or meant to counteract some of the 11 effects of the amphetamines? 12 A. It has an neurochemical 13 effect. 14 Q. What's that effect? 15 A. It would penetrate -- use the 16 uptake of serotonin to enter the serotonin 17 neuron, which -- 18 Q. So it would kind of piggyback 19 onto the serotonin? 20 A. Yes. 21 Q. To get into the serotonin 22 neuron? 23 A. Yes. 24 Q. What would happen in the Page 243 1 serotonin neuron then? 2 A. That would lead to decrease of 3 serotonin concentration in the animal given. 4 Q. Why would you want to do that? 5 A. That ultimately would decrease 6 in uptake of serotonin, okay. So if we treat 7 animals with Fluoxetine, then you would prevent 8 the entry of para-chloroamphetamine into the 9 serotonin neuron to decrease serotonin -- 10 Q. Because the serotonin wasn't 11 getting into the serotonin neuron itself? 12 A. So it's a way to look at 13 another ex vivo assay for what in vivo effect of 14 Fluoxetine. 15 Q. Okay. To your knowledge did 16 Lilly ever consider putting -- combining 17 Fluoxetine with an anti-anxiety agent before 18 placing it on the market? 19 A. Not that I know of. 20 Q. Are you aware of any animal 21 studies that were done at Lilly combining 22 Fluoxetine with a sedative? 23 A. Would you give example, what 24 sedative particularly are you talking about? Page 244 1 MR. SMITH: Diazepam. 2 Q. Diazepam. 3 A. No, I don't remember any such 4 study being done. 5 Q. Any other sedative or drugs 6 with sedative properties like we talked earlier 7 about that doctor you talked to who was putting 8 his patiets on Trazodone, I believe, as well as 9 Fluoxetine because it had a sedative property? 10 MR. MYERS: I object to the form. I 11 thought it had something to do with causing them 12 to actually sleep as opposed to -- I don't know 13 if that's what he said earlier. 14 Q. Sedatives cause you to sleep, 15 right? 16 A. Yes. 17 Q. Okay. So I mean he wasn't 18 giving the Trazodone as a sleeping pill, was he? 19 A. No. 20 Q. He was giving it as a sedative 21 to counteract some of the -- 22 A. No, Trazadone is also an 23 antidepressant. 24 Q. Right. And Fluoxetine is an Page 245 1 antidepressant, correct? 2 A. Yes. 3 Q. Why was he giving the 4 combination of two antidepressants to one 5 patient? 6 A. To help patient to sleep. 7 Q. The patient was having trouble 8 sleeping? 9 A. Yes. 10 Q. Did he attribute that trouble 11 sleeping to Fluoxetine? 12 A. Whether that's attributable to 13 Fluoxetine or not, I don't recall such an 14 association in our discussion. 15 Q. Did he feel that the 16 Fluoxetine wasn't working appropriately as an 17 antidepressant? 18 A. And also that -- I don't 19 recall we talked about efficacy of Fluoxetine was 20 the topic for our discussion. 21 Q. There were other ways, other 22 pills that somebody could take other than another 23 antidepressant that could help them sleep, 24 correct, there are pills developed specifically Page 246 1 as sleeping pills, are there not? 2 A. I'm sorry, that would be out 3 of my expertise to describe what combination. 4 Q. Did you ask him why he chose 5 Trazodone as opposed to any other substance to 6 counteract this person's trouble sleeping? 7 A. That was a very brief 8 discussion that -- our conversation was 9 relatively brief, we only talked about such an 10 experience that he had with combination of 11 Trazodone, and I didn't ask about other drug. 12 Q. What did he say his experience 13 with that patient on both drugs was? 14 A. I'm sorry? 15 Q. What did he say about his 16 experience with that patient that he placed on 17 both Fluoxetine and Trazodone? 18 A. I didn't ask the consequence. 19 Q. What did you talk to him about 20 with that study? 21 A. Mainly asked what drug that he 22 have combined with Fluoxetine, and Trazodone is 23 what he mentioned. 24 Q. And you spoke to him after he Page 247 1 presented a paper at a meeting? 2 A. No, just a -- 3 Q. How did you know that he had 4 combined Fluoxetine with any drug whatsoever? 5 A. Just a curiosity question. 6 MR. MYERS: He just told you, I think 7 he said he asked him. 8 Q. Right. Did you approach this 9 doctor or did he approach you? 10 A. We were just sent together and 11 just conversation, talk about his experience, 12 such experience that he had. 13 Q. Did he know who you were, did 14 he know that you were involved with Fluoxetine? 15 A. That, I don't know whether he 16 aware of who I was. 17 Q. How did the subject come up? 18 A. We were having coffee, and I 19 just asked him if he have experience in treating 20 patients with Fluoxetine. 21 Q. And he said yes? 22 A. Yes. 23 Q. And? 24 A. And I said what -- is there Page 248 1 any combination drug that you have, Trazodone, 2 and that's to help the patient to sleep, and 3 that's about the extent of it. 4 Q. Okay. Did you ever ask any 5 other doctor if they put patients on Fluoxetine 6 in combination with other drugs? 7 A. No, I have not asked doctor 8 especially about on that question, but in most -- 9 in many of the publication on clinical trial of 10 Fluoxetine, such combination being reported and 11 allowed in protocol, so I don't know. 12 Q. Allowing for specifically 13 Trazodone or other drugs as well? 14 A. I believe the benzodiazepines. 15 Q. Chloral hydrate? 16 A. I don't know for chloral 17 hydrate. 18 Q. Why are they allowing the use 19 of benzodiazepines in the clinical trials of 20 Fluoxetine? 21 A. That is beyond my expertise to 22 tell you why, precise reason. 23 Q. In any of your studies that 24 you have done on rats and Fluoxetine, have you Page 249 1 found any evidence that indicates that Fluoxetine 2 has a stimulant profile in rats, either 3 psysiologically or behaviorally or from a 4 biochemistry standpoint? 5 A. There's no evidence that -- we 6 have not encounter animal that as you described 7 effect on Fluoxetine, the way that you described 8 about -- 9 Q. Attributing a stimulant 10 profile to Fluoxetine? 11 A. That's right, in animal. 12 Q. Have you found evidence that 13 Fluoxetine has a sedative profile? 14 A. And also that -- that is a 15 behavioral pharmacological study, and that is not 16 my expertise to recognize whether there's a 17 sedative effect or not. But I did make a 18 statement in previous time that I only saw no 19 overt behavioral change. 20 Q. Did you see any behavioral 21 change whatsoever? 22 A. Just what I can judge. 23 Q. Just overt. So in other 24 words, if a rat all of a sudden started reacting Page 250 1 completely different than it had the day before, 2 that would be an overt change? 3 A. What I meant was the animal 4 treated with Fluoxetine is no different from an 5 animal treated with saline. 6 Q. Did you place -- tell me a 7 little bit about the set up in your lab, were all 8 your rats that were treated with Fluoxetine kept 9 in one cage or were they all given their 10 individual cages? 11 MR. MYERS: For what study or what 12 point in time? 13 Q. Do you have a general method 14 of doing things, do you usually separate the rats 15 or do you keep them all together? 16 A. Depends on the purposes of the 17 experiment. If that experiment is the same after 18 treating animals for one hour, then we normally 19 would place them in one cage. 20 Q. How about the down regulation 21 studies you did? 22 A. Usually we keep two animal per 23 cage. 24 Q. Two per cage? Page 251 1 A. Yes. 2 MR. SMITH: Why? 3 THE WITNESS: The animal need to 4 social interaction. That's what I was told. 5 Q. That's what you were told? 6 A. Yes. 7 Q. Who told you that? 8 A. The literature. 9 Q. Do you know Doctor Jan 10 Fawcett? 11 A. Jan Fawcett. I read his 12 publications. 13 Q. Did you read his publication 14 where he recommends administering a sedative to 15 patients on drugs that cause jitteriness, such as 16 Fluoxetine? 17 MR. MYERS: I object to the form only 18 because I don't know that you've accurately 19 characterized what Doctor Fawcett wrote. If 20 you've got the publication. 21 Q. You're right. Where he 22 recommends for patients who are a suicidal risk 23 and they're on medications that cause 24 jitteriness, such as Fluoxetine, that they be Page 252 1 given a concomitant sedative? 2 MR. MYERS: Same objection. 3 Q. Are you aware of that 4 publication? 5 A. I missed exactly what was 6 which question. 7 Q. Have you read that 8 publication, have you read that paper? 9 A. That particular paper, I don't 10 recall if I have read that paper. 11 Q. What papers of Doctor 12 Fawcett's do you recall reading? 13 A. In the span of the last twenty 14 years, I've read many papers. I don't remember a 15 particular paper associated with Doctor Fawcett, 16 except I recognize the name Jan Fawcett. 17 Q. Have you read his papers that 18 were strictly related to Fluoxetine or have you 19 read other of his papers? 20 A. Some of the papers, whether or 21 not associate with Fluoxetine, I don't recall. 22 Q. Can a down regulation of 23 serotonin receptor be related to the production 24 of serotonin? In other words can the down Page 253 1 regulation of the receptor result in a decrease 2 in the production of serotonin? 3 A. Down regulation of serotonin 4 receptor, in my opinion, is a refraction of a 5 persistent activation of that receptor by the 6 greater availability of serotonin at that 7 receptor site. 8 Q. And this morning we were 9 talking about whether or not the receptor's 10 firing had anything to do with triggering the 11 neurons in the back of the brain or serotonin 12 cells in the back of the brain to signal for the 13 production of serotonin, do you remember that? 14 A. The release of serotonin. 15 Q. The release of serotonin. Is 16 it possible that the down regulation caused by 17 the constant firing of the neuron because of the 18 presence of serotonin in the synaptic cleft could 19 cause the neuron to stop telling the serotonin 20 cell to release serotonin? 21 A. The down regulation receptor -- 22 Q. Let me try it again, let me 23 break it down for you. 24 A. Yes, please. Page 254 1 Q. The down regulation is caused 2 because the neuron is constantly firing because 3 the serotonin is in the synaptic cleft affecting 4 the receptor constantly, correct? 5 A. Yes. 6 Q. Is it possible that because 7 the receptor is down regulating itself or slowing 8 itself down because of the constant stimulation, 9 that it is somehow triggering a message to the 10 neurons at the back of the brain not to release 11 any more serotonin until it gets the level back 12 in order? 13 A. Well, that possibility could 14 happen, yes. 15 Q. What is the probability of 16 that happening based on scientific -- state of 17 scientific knowledge as it stands? 18 A. All I can say is it a good 19 possibility that could happen. 20 Q. It's a good possibility? 21 A. Yes. 22 Q. As part of the hemostatis that 23 we've been talking about? 24 A. Yes. Page 255 1 Q. In other words the body says 2 we don't need any more serotonin, we've got more 3 than we need right now, right here, correct? 4 A. Adequate, yes. 5 Q. Are you aware of anybody 6 currently or formerly working at Lilly who was 7 against marketing Prozac? 8 A. I never -- that never occurred 9 to me, that opinion. 10 Q. Are you aware of anyone who 11 currently or formerly at Lilly who was against 12 marketing Prozac to the nonpsychiatric medical 13 practitioner, in other words like the internists 14 or GPs or family practice physician? 15 A. Because I'm not in the area of 16 expertise to make decision, I never -- that never 17 been raised to me or brought up to me, that 18 question. 19 Q. How about in the project team 20 meetings, did that issue ever come up? 21 A. I don't recall in a project 22 team meeting that being mentioned. 23 Q. Have you done a down 24 regulation study on rats for longer than Page 256 1 twenty-five days with Fluoxetine? 2 A. Twenty-five days, that's the 3 longest I have tried. 4 Q. How come you haven't gone 5 longer? 6 A. Human resources limitation. 7 Q. Have you seen any published 8 studies on down regulation in rats on Fluoxetine 9 besides your own? 10 A. Yes. 11 Q. What studies are those? 12 A. What studies? 13 Q. How many of them are there, 14 are there a lot of them, are there a few? 15 A. Quite a few, yes. 16 Q. More than twenty? 17 A. The exact number, I cannot -- 18 I don't remember the exact number. 19 Q. Have you done any tests on 20 rats to see what the effect of long-term exposure 21 to Fluoxetine would be on the receptors after the 22 rats were taken off the Fluoxetine? 23 A. That I haven't done. 24 Q. How come, why not? Page 257 1 A. Again, limit of the human 2 resources. 3 Q. Has anybody at Lilly told you 4 not to do such a study? 5 A. No. 6 Q. Has anybody at Lilly told you 7 not to do any other studies on down regulation? 8 A. No. 9 Q. Are you aware of any studies 10 that are done on animals as to the long-term 11 effects of Fluoxetine exposure and the ability of 12 the neurotransmitter to go back to normal after 13 Fluoxetine is stopped? 14 MR. MYERS: At Lilly or anywhere? 15 MS. ZETTLER: Anywhere. 16 A. Could you repeat that 17 question? 18 Q. Sure. What I'm interested in 19 knowing is say you have the rat on Fluoxetine for 20 twenty-five days. 21 A. Yes. 22 Q. At the end of the twenty-five 23 days, in your experiment, the rat was still on 24 Fluoxetine, correct? Page 258 1 A. Yes. 2 Q. And then you sacrificed the 3 rat. 4 A. Yes. 5 Q. To study what would happen as 6 far as down regulation, correct? 7 A. Yes. 8 Q. Are you aware of any studies, 9 using that study as an example, the time period 10 of that study as an example, where a rat was 11 placed on Fluoxetine for twenty-five days and 12 then taken off of the drug for a period of time 13 and then sacrificed and studied to see what the 14 effect on the receptors were? 15 A. I don't recall seeing any 16 publication of that type of study being done. 17 Q. Have you seen -- have any of 18 those studies been done at Lilly as far as you 19 know? 20 A. Not that I know of. 21 Q. And you have not done a study? 22 A. I have not done such a study. 23 Q. Are you aware of what the 24 long-term effects of Fluoxetine exposure is to Page 259 1 the human serotonin receptors, if any? 2 MR. MYERS: I object to the form only 3 to the extent that that may call for a medical 4 opinion. But if you know, certainly, Doctor, 5 tell her. 6 A. I'm not aware of such a study 7 being done in human. 8 Q. Are you aware that in at least 9 one of the clinical trials conducted by Lilly on 10 Fluoxetine cerebrospinal fluid samples were 11 taken? 12 A. I think that was mentioned 13 last time. I'm not aware of it until the meeting 14 last time we had. 15 Q. Can you think of any other 16 reason why they would take cerebrospinal fluid 17 samples of people being tested on Fluoxetine 18 other than to measure either the metabolite or 19 serotonin levels in the cerebrospinal fluid? 20 A. Since I'm not aware of such 21 study being done, so I don't know how to -- I 22 cannot comment on something I don't know. 23 Q. In a normal person who isn't 24 on Fluoxetine or any other inhibitor or chemical Page 260 1 to mess around with the uptake or the level or 2 whatever, how long does the serotonin work once 3 it's placed in the synaptic cleft? 4 MR. MYERS: Let me just either object 5 or -- when you say normal, you mean a 6 nondepressed patient? 7 MS. ZETTLER: Right. 8 A. How -- would you repeat again, 9 please? 10 Q. Let me change it a little bit. 11 Let's do it with rats. In your average normal 12 rat, if you were just going to test the 13 serotonin, how long does the serotonin stay in 14 the synaptic cleft? 15 A. Again, I mentioned earlier, 16 technically that kind of study still not feasible 17 to study the concentration of serotonin in the 18 synaptic cleft. 19 Q. I'm not asking about 20 concentrations, I just want to know, say the 21 serotonin producing cell throws some serotonin 22 into the synaptic cleft, how long does that 23 serotonin usually stay there before it's 24 metabolized? Page 261 1 MR. MYERS: Or before it's taken back 2 up? 3 MS. ZETTLER: Sure, if there's a 4 difference. I think it has to be taken back up 5 to be metabolized. 6 MR. MYERS: Right. 7 A. In my understanding of that 8 question, still have to rely on ability to detect 9 concentration of serotonin in the synaptic cleft. 10 Q. So the answer is you don't 11 know how long it stays there? 12 A. I don't know how long it stays 13 there. 14 Q. You tested -- you've been able 15 to mark serotonin, so to speak, with radioactive 16 isotopes? 17 A. Radioactive serotonin. 18 Q. And have you been able to 19 place that directly into the cleft itself or is 20 it something that is produced by the cell, in 21 other words would you be able to track by 22 watching the serotonin where it goes in the cleft 23 and how it's going to being taken up or whatever, 24 would you be able to keep track of it that way? Page 262 1 A. No. Again, also, the 2 technical is not feasible to do that kind of 3 study at this point. 4 Q. Say you're giving a rat 5 Fluoxetine, okay, and do you then look for the 6 metabolite of serotonin to see if it's being 7 taken up, retaken up back into the cell? 8 MR. MYERS: Look for the metabolite 9 where? 10 MS. ZETTLER: In the cerebrospinal 11 fluid. 12 MR. MYERS: Of this rat? 13 MS. ZETTLER: Right. 14 A. I have not done such an 15 experiment. 16 Q. The study you were telling 17 Paul about the last time we were together, where 18 you made the solution like spinal fluid and you 19 were able to measure the level of serotonin, I 20 believe, or was it the metabolite that you were 21 measuring? 22 A. Serotonin, and metabolite. 23 Q. And the metabolite, okay. 24 Were you able to judge when the inhibiting Page 263 1 properties of Fluoxetine were taking effect by 2 the level of either the serotonin or the 3 metabolite that you were finding in this 4 cerebrospinal fluid preparation? 5 MR. MYERS: As compared to when it was 6 introduced? 7 MS. ZETTLER: Right. 8 A. In the microdialysate, that -- 9 the serotonin -- I'm confused with that question. 10 Q. I just want to know if you can 11 estimate from looking at the serotonin and the 12 metabolite in this manufactured cerebrospinal 13 fluid that you used in the probe test, how long 14 it took the Fluoxetine to start affecting the 15 uptake of serotonin in the rats' brains? 16 A. Almost within the first 17 sampling time. 18 Q. Which was how long? 19 A. Fifteen minutes. 20 Q. Fifteen minutes after you gave 21 them the Fluoxetine? 22 A. Yes. 23 Q. And you were able to tell that 24 how, from -- was there a decrease in the Page 264 1 metabolite? 2 A. You can measure the 3 superfusate, go through the brain area and come 4 out in the -- elude out from the brain, and to 5 measure the concentration of serotonin. 6 Q. So you didn't even consider 7 the metabolite, it was just the serotonin? 8 A. The metabolite in the fluid 9 also. 10 Q. So you were able to tell by 11 the metabolite that the Fluoxetine had started 12 working? 13 A. Both metabolite and serotonin. 14 Q. What was the difference about 15 the levels of serotonin and the metabolite, did 16 they decrease? 17 A. The serotonin concentration 18 would rise, whereas the metabolite would 19 decrease. 20 Q. I think I asked you this 21 earlier, and if I did, I apologize, but no one 22 knows how long the serotonin works once it's in 23 the synaptic cleft, correct? 24 A. Correct. Page 265 1 Q. How many neurotransmitters 2 have been identified to date? 3 A. Nearly a hundred. 4 Q. Nearly a hundred. And when 5 you say neurotransmitters, you're talking about 6 things like dopamine, serotonin? 7 A. Estacholine, histamine, GABA, 8 glutamate, aspartate, copetorine, so, and also 9 neuropeptides. 10 Q. Any others? 11 A. There's neuropeptides, there 12 are many neuropeptides. 13 Q. What is the significance of 14 measuring the serotonin metabolite in spinal 15 fluid, human spinal fluid, what would that tell 16 you? 17 A. Again, I have never done such 18 experiment in human subject, and also it would be 19 beyond my activity, so I cannot really assess the 20 motive in doing that. 21 Q. Can you extrapolate from a 22 lower serotonin metabolite in rats once they were 23 given Fluoxetine, you know, metabolite in the 24 spinal fluid once they were given Fluoxetine to a Page 266 1 lower serotonin level in human spinal fluid 2 indicating that Fluoxetine is inhibiting the 3 uptake of serotonin? 4 A. The situation in the rat 5 experiment, actually that study Doctor Fuller 6 did, is to put the microdialysis probe into the 7 brain area, and as opposed to human, do spinal 8 tap. So is very different situation, and we can 9 only -- I can only explain the situation in the 10 rat. 11 Q. Last time you talked with us, 12 you talked about a normal range of serotonin in 13 spinal fluid or in the bloodstream. Do you 14 recall that? 15 A. We discussed that. 16 Q. Okay. 17 A. But -- 18 Q. Did you ever go back and try 19 to ascertain what that range was, the normal 20 range? 21 A. It wasn't me who have that 22 idea. 23 Q. I thought you said that there 24 was a normal range of serotonin? Page 267 1 A. No, I didn't say that, I 2 didn't say there was a normal range. I believe 3 it was Mister Smith. 4 MR. MYERS: I distinctly remember he 5 said the first time that there was not -- look on 6 page -- 7 MS. ZETTLER: I know, but you said 8 something different later on in the deposition. 9 Q. Maybe it was when you were 10 talking about the Ashburg study. 11 A. I remember talking Ashburg. 12 Q. Didn't she assign a range? 13 Remember she talked about some people having -- 14 A. She mentioned a distribution, 15 not range, a distribution. 16 Q. What was her distribution, do 17 you recall? 18 A. No, I didn't go back to look 19 for the paper. 20 Q. Because she was able to, at 21 least in her study, determine that there was a 22 subgroup of people who had a lower serotonin -- 23 subgroup of depressed people who had a lower 24 serotonin level than others in the group, Page 268 1 correct? 2 A. Yes. 3 Q. And that was using this 4 distribution as opposed to the normal range of 5 serotonin level? 6 A. I mentioned a bimodal 7 distribution. 8 Q. Right. Where is the serotonin 9 metabolized, is it metabolized in the serotonin 10 containing cell once it's taken back up into the 11 cell? 12 A. It could be metabolized in 13 anywhere actually, and could be metabolized 14 within the neuron, of its own neuron, it could be 15 metabolized by circulating enzymes. The 16 monoamine oxydase is almost ubiquitously 17 distributed. 18 Q. Could it be mebabolized within 19 the cleft, the synaptic cleft? 20 A. That, I have no knowledge of. 21 Q. Can it be metabolized by the 22 receptors? 23 A. I don't believe that could 24 happen. Page 269 1 Q. Does it need to be taken back 2 up into the serotonin producing cell to be 3 metabolized? 4 A. That's one of the ways to be 5 metabolized. 6 Q. Okay. What other ways, 7 outside of being taken back up into the serotonin 8 cell, can it be metabolized? 9 A. In the circulation, could be 10 metabolized. 11 Q. Okay. Which has nothing to do 12 with the serotonin producing cell? 13 A. That's right. 14 Q. Any other way? I'm talking 15 about in the brain now. 16 A. Yes, I understand. 17 Q. Okay. Any other way besides -- 18 when you say the circulation, you mean the blood 19 circulation in the brain? 20 A. Yes. 21 Q. Any other way it can be 22 metabolized? 23 A. Those are probably major 24 sites. Page 270 1 Q. So in the serotonin producing 2 cell or in the bloodstream? 3 A. That's where the neurons could 4 metabolize it. 5 Q. Other neurons can metabolize 6 it? 7 A. Yes. Where monoamine oxydase 8 are present, the enzyme that can be found in many 9 tissues as well as in circulation. 10 MR. MYERS: Wait a minute. Paul, look 11 on page one fifty-nine and then on page one 12 sixty-four. 13 MR. SMITH: I have already read one 14 fifty-nine, we're on page one sixty-three now. 15 MR. MYERS: You're getting there. 16 MR. SMITH: He starts talking about 17 the two arms. 18 Q. (BY MS. ZETTLER) Besides 19 firing the neuron, what happens when serotonin 20 contacts the postsynaptic receptor? 21 A. It will initiate -- it will 22 initiate the intracellular propagation of the 23 message. 24 Q. Okay. Page 271 1 A. Including the release of 2 calcium. 3 Q. Is the intracellular 4 publication of the -- 5 A. Propagation. 6 Q. Propagation, I'm sorry. 7 Propagation of the message the same as firing the 8 neuron? 9 A. That could be one of the 10 chemical transduction process, transducive 11 process. 12 Q. What other chemical 13 transducive processes take place? 14 A. I'm sorry? 15 Q. What other chemical 16 transducive process -- 17 A. Within the cell -- 18 Q. Right. 19 A. -- occur. 20 Q. You said that could be one of 21 the chemical transducive processes that take 22 place. Are there others that could take place? 23 A. Also conduct the message by 24 the excitable membrane of the neuron. Page 272 1 Q. Okay. Anything else? 2 A. That is the two major theories 3 about neurotransmission. 4 Q. Okay. On page one sixty-four 5 of the deposition, talking about the Ashburg 6 study, actually one sixty-three also, Paul asked 7 you what the normal level of serotonin is, and 8 you stated you didn't remember. 9 MR. MYERS: Where are you, on what 10 line? 11 MS. ZETTLER: Line eighteen, page one 12 sixty-three. 13 MR. MYERS: Okay. 14 A. Maybe I should say I don't 15 know. 16 Q. And the next page, it goes on, 17 it says -- you talked about a normal range as 18 opposed to a normal level. Do you see that? Up 19 at the top of the page, you corrected Paul, Paul 20 used normal level, and you said normal range, 21 correct? 22 A. Yes. 23 Q. And that's in a range that was 24 attributed by Doctor Ashburg, correct? Page 273 1 A. That is Doctor Ashburg's 2 assessment of the distribution of serotonin with 3 the patients. 4 Q. So that range is established 5 only with her patients, in other words that's not 6 a range that has been accepted generally as a 7 normal range of serotonin by the medical 8 community or a psychiatric community or the 9 biochemical community? 10 A. I don't know this is a normal 11 range established of a so-called normal 12 individual. 13 Q. Does lower serotonin 14 metabolite indicate a decreased level of 15 serotonin? 16 A. Will you repeat again? 17 Q. Does a lower level -- say you 18 measured the level of the serotonin metabolite, 19 okay, and that level decreases. Does that 20 indicate necessarily that it's a decrease in 21 serotonin? 22 A. You mentioned about decrease 23 or lower level. 24 Q. What is the difference between Page 274 1 decrease and lower level? 2 A. To me decrease have a 3 connotation as being caused by something. Being 4 lower is being -- have less amount. 5 Q. Not being caused by something? 6 A. Correct. 7 Q. Well, what about the 8 inhibition of the reuptake of serotonin into the 9 serotonin producing cell by Fluoxetine, does that 10 cause a decreased serotonin level? 11 A. That does not cause decrease 12 of serotonin level. 13 Q. How do you know that? 14 A. The serotonin concentration in 15 the brain tissue did not change. 16 Q. You don't know if it causes a 17 decrease in the level in the synaptic cleft, do 18 you? 19 A. Because of the response of the 20 animal -- 21 Q. The what of the animal? 22 A. The responses that measure, is 23 expression of higher transmission of serotonin. 24 Q. What kind of responses? Page 275 1 A. Such as suppression of food 2 intake, such as changing in secretion of hormone. 3 And those are all consistent with a greater 4 availability of serotonin in the synapse. 5 Q. Secretion of what hormone? 6 A. The pituitary -- hormones 7 regulated by the pituitary hypothalamus axis. 8 Q. And behavioral changes, like 9 suppression of appetite? 10 A. Yes. 11 Q. But that's really speculation, 12 is it not, you you still don't know whether or 13 not there is a decrease in the serotonin in the 14 synaptic cleft because you can't measure that 15 level in the cleft, can you? 16 MR. MYERS: Let me object to the form, 17 and advise you, Doctor Wong, you're not required 18 to accept her terminology speculation. She asked 19 the question, and you answered it. Is the 20 question do you know -- what is the pending 21 question, is it speculation or do you know it? 22 MS. ZETTLER: Is it speculation. 23 A. Again, the consequence about -- 24 after giving Fluoxetine to animal, produced a Page 276 1 number of responses are consistent with a greater 2 availability of serotonin -- 3 Q. But those -- 4 A. -- in the transmission of 5 serotonin. 6 Q. Making the connection between 7 the greater availability of serotonin and the 8 transmission of serotonin with these responses is 9 really putitive, is it not? It's not something 10 that has been proven scientifically, has it? 11 A. The microdialysis study that I 12 mentioned, that also demonstrate the greater 13 availability of serotonin being released upon 14 giving animal the Fluoxetine. 15 Q. More serotonin being released 16 when the animal was given Fluoxetine? 17 A. Yes. 18 Q. How do you measure that? 19 A. By measuring the serotonin 20 concentration in the microdialysate. 21 Q. Of what, the snnaptic cleft or 22 the brain tissue in general? 23 A. The microdialysate would 24 equilibrate with the environment, the seal of the Page 277 1 synaptic cleft. 2 Q. So you can measure the amount 3 of serotonin in the synaptic cleft? 4 A. It is a -- the fluid, 5 microdialysate fluid, would equilibrate with the 6 environment of the snyaptic cleft. 7 Q. What do you mean by 8 equilibrate the environment? 9 A. The fluid penetrate in and 10 out. 11 Q. In and out of where? 12 A. Whatever tissue barrier into 13 the circulation of the neurolar space, 14 intraneurolar space. 15 Q. So using that method, how come 16 you can't determine what a normal level of 17 serotonin in a synaptic cleft of a rat is? 18 A. One can measure the level of 19 serotonin in the rat, and also one can, in the 20 rat brain, as well as one can measure the 21 concentration of serotonin in the microdialysate 22 of the particular brain area of the rats. 23 Q. I'm talking about the synapse 24 itself, okay, the synaptic cleft, that's what I'm Page 278 1 talking about. 2 A. Right. 3 Q. I want to know how it is you 4 can measure that there is an increase of 5 serotonin, more serotonin is being released into 6 the synaptic cleft, but you can't figure out what 7 a normal level of serotonin is in the normal rat 8 that isn't being given Fluoxetine. 9 A. At this point, that remain a 10 step from the measurement of concentration of 11 serotonin directly in the synaptic cleft. 12 Q. So you have or you have not 13 measured the concentration of serotonin directly 14 in the synaptic cleft? 15 A. Have not directly measured 16 serotonin in synaptic cleft. 17 Q. So you're extrapolating from 18 the concentration of serotonin that you're 19 finding in this process generally increasing that 20 more of it is getting into the snyaptic cleft? 21 A. Yes. 22 Q. Have you heard the term 23 sluggish serotonin? 24 A. I'm sorry? Page 279 1 Q. Have you heard the term 2 sluggish serotonin? 3 A. No. 4 Q. Did your tests on rats 5 indicate that the serotonin metabolite decreased 6 initially upon administration of Prozac or 7 Fluoxetine to rats? 8 A. Repeat again, please. 9 Q. Did you find initially that 10 the level of the serotonin metabolite decreased 11 initially upon giving the rats Fluoxetine? 12 A. That initial observation was 13 made by Doctor Fuller, I wasn't the one that made 14 that observation. 15 Q. Did that level, over time, 16 ever come back up on rats that were exposed to 17 Fluoxetine? 18 A. Remember Doctor Fuller's data, 19 but you would have to ask him, but I believe that 20 it does come back. 21 Q. After how long a period of 22 time, generally? 23 A. Twenty-four or forty-eight 24 hours. Page 280 1 Q. Does that indicate an initial 2 shut-down of the serotonin system? 3 A. I'm sorry? 4 Q. Does that indicate an initial 5 shut-down of the serotonin system as a 6 compensatory mechanism? 7 A. It's not a shut-down, it's a 8 compensatory mechanism in operation. 9 Q. What does that compensatory 10 mechanism do, what is the effect of that 11 compensatory mechanism on the level of serotonin? 12 A. That compensatory mechanism is 13 to maintain a steady state concentration of 14 serotonin in the synaptic cleft. 15 Q. So slow down the production of 16 the metabolism in the serotonin? 17 A. That would regulate the 18 release and also the synthesis of serotonin. 19 Q. Would it indicate a slow down 20 in the synthesis and release of serotonin? 21 A. Under what condition being 22 slowed down? 23 Q. With the initial compensatory 24 reaction or the shut-down of serotonin, of the Page 281 1 serotonin system. 2 MR. MYERS: I object to the form and 3 your use of the word shut-down, because he said 4 it was not shut-down. 5 Q. The initial compensatory 6 mechanism or the initial lower level of 7 metabolite that we just talked about. 8 A. I'm still not quite clear what 9 you mean by initial lower level. 10 Q. Let me ask it again. You 11 testified that you're aware or at least your 12 recollection of Doctor Fuller's study was that 13 there was an initial decrease in the serotonin 14 metabolite upon giving rats Fluoxetine, correct? 15 A. Yes. 16 Q. And this indicated to you 17 there was a compensatory mechanism that was 18 occurring, correct? 19 A. Yes. 20 Q. And that compensatory 21 mechanism was to keep the amount of serotonin 22 available in the synaptic cleft at a static 23 level, correct? 24 A. Yes. Page 282 1 Q. And to do that -- my question 2 is to do that, is there a resulting decrease in 3 the synthesis and release of serotonin as a part 4 of that compensatory mechanism? 5 A. That is a part of the 6 compensatory mechanism. 7 Q. And that lasted for a couple 8 of days, as far as your recollection? 9 A. By twenty-four hours recover. 10 Q. Completely? 11 A. I believe it took forty-eight 12 hours completely recover, but you have to see 13 Doctor Fuller's publication or you have to ask 14 him to be precise. 15 Q. Did you ever have a study 16 where the metabolite initially increased in rats 17 upon administration of Fluoxetine? 18 A. I'm not aware of such an 19 increase have been reported. 20 Q. Are you aware of any studies 21 being reported where the metabolite level stayed 22 the same upon administration of Fluoxetine 23 initially? 24 A. I'm not aware of metabolite of Page 283 1 serotonin remain the same. 2 Q. Was a decrease in the 3 metabolite fairly consistent in the rat studies 4 as far as you know? 5 A. Decrease in metabolite? 6 Q. Right. 7 A. Of serotonin metabolite? 8 Q. Right. 9 A. It is consistent with 10 Fluoxetine and also with other inhibitor for 11 uptake of serotonin. 12 Q. Okay. But your testimony is 13 that it was consistent, there was always an 14 initial decrease in the metabolite, serotonin 15 metabolite, upon administration of serotonin 16 reuptake inhibitors in general? 17 A. Yes. 18 Q. Is there a lower level of 19 metabolite attributed initially to Fluoxetine as 20 opposed to other serotonin reuptake inhibitors? 21 A. I don't think so. 22 Q. So it's pretty much the same 23 across the board? 24 A. Yes. Page 284 1 Q. Are you aware that lower 2 levels of serotonin metabolite have been found in 3 individuals who commit suicide or 4 violent-aggressive acts? 5 A. That is based on Doctor 6 Ashburg's report. 7 Q. Does a lower level of 8 metabolite in a normal person indicate a lower 9 production of serotonin or lower level of 10 serotonin? 11 A. That -- I'm not familiar with 12 those kind of studies. 13 Q. How about in depressed 14 patients who have committed suicide, are you 15 aware of any studies that have been done that 16 indicate that a decreased serotonin level or 17 decreased serotonin functioning is associated 18 with depressed patients? 19 A. Again, I have to draw the 20 information from Doctor Ashburg's publication, I 21 believe that would be discussed in her 22 publication. 23 Q. What about that book you read 24 early on that prompted you to want to get into Page 285 1 brain chemistry, didn't that book discuss the 2 association between serotonin and depression? 3 A. That is the -- yes, in the 4 early '60s there's a study. 5 Q. Did they say it was an 6 increased level of serotonin that caused 7 depression? 8 A. No. 9 Q. Did they say it was a 10 decreased level? 11 A. Those were the postmortem 12 tissue study of suicide victim. The high brain 13 level of serotonin metabolite was lower than 14 those of victim of coronary disease or accident. 15 Q. Somebody who didn't kill 16 themself? 17 A. Yes. 18 Q. Somebody who didn't take their 19 own life? 20 A. That's right. 21 Q. So it was actually the 22 metabolite that was lower? 23 A. I believe that's what 24 metabolites were measured. Page 286 1 Q. Did they extrapolate from that 2 lower levels of metabolite a lower level of 3 serotonin in that area of the brain? 4 A. Let me have the question 5 again. 6 Q. Sure. You said it's your 7 recollection that they associated a lower level 8 of the serotonin metabolite in a portion of the 9 brain -- was it the rear? 10 A. The hind brain. 11 Q. The hind brain. With people 12 who had committed suicide or taken their own 13 lives, correct? 14 A. Yes. 15 Q. As opposed to people who had 16 died in an accident or of natural causes, 17 correct? 18 A. Yes. 19 Q. Did they extrapolate from that 20 decreased metabolite level in the people who had 21 committed suicide, a lower serotonin level, at 22 least in that portion of the brain? 23 A. I don't recall whether such 24 extrapolation was mentioned. Page 287 1 Q. Do you recall what they 2 mentioned at all about the serotonin level or 3 what the decreased metabolite indicated? 4 A. Again, I don't recall such an 5 extrapolation being made. 6 Q. Not just that extrapolation, 7 you know, extrapolating the comparison between 8 the lower metabolite and lower serotonin, do you 9 recall what conclusions they made whatsoever 10 regarding the role of the decreased metabolite in 11 the hind brain of the people who committed 12 suicide? 13 A. The only extrapolation was 14 there was association or involvement of serotonin 15 or endoamine metabolites with depressive illness, 16 and that is my recollection. 17 Q. Was it just the serotonin 18 metabolite that they measured or was it 19 metabolite of other neurotransmitters? 20 A. Only serotonin metabolite was 21 measured. 22 Q. How about in people who 23 committed murders or violent acts, have you seen 24 any published studies indicating that a lower Page 288 1 serotonin metabolite level is associated with 2 that kind of behavior? 3 A. That kind of information in 4 publications that cited Doctor Linnona's 5 publication. 6 Q. Can you spell that? 7 A. L-I-N-N-O-N-A. His first name 8 is Marku. 9 Q. M-A-R-C-O? 10 MR. MYERS: K-U, I think. 11 Q. Oh, Marku. 12 A. Yes, Marku. 13 Q. I'm sorry. Do you know where 14 he's from? 15 A. I believe that he worked at 16 NIMH. 17 Q. Is he still there? 18 A. I believe so. 19 Q. Do you know when this paper 20 was published? 21 A. In the late '80s. 22 Q. Does he associate lower 23 serotonin levels or lower serotonin metabolite 24 levels with violent-aggressive behavior? Page 289 1 A. That was the -- that paper has 2 been cited as a reference for that idea. 3 Q. Okay. By who? 4 A. In psychiatric psychiatry 5 journal, paper published, psychiatric paper. 6 Q. So there are more papers since 7 Doctor Linnona's paper that have discussed the 8 issue? 9 A. Yes. 10 Q. What's the general concensus 11 of these papers if you know? 12 MR. MYERS: I object to the form only -- 13 you're asking -- he can give you his impression 14 of the paper, they say whatever they say, and if 15 you do a literature search you can find them, but 16 I don't know that it's appropriate to ask him -- 17 Q. Is there a general train of 18 thought that is agreeing that a lower serotonin 19 level is related to violent-aggressive behavior? 20 A. Again, I read the literature 21 and the reports as such, and I would not have a 22 medical opinion. 23 Q. I'm asking you generally what 24 the literature is saying, is it starting to point Page 290 1 to a connection, are there people who disagree 2 with that theory, are there people who agree with 3 that theory? 4 A. My recollection, if this is 5 correct, I remember that it's consistent with the 6 lack of serotonin associated with violent 7 behavior. 8 Q. Does evidence of the 9 concentration of serotonin in the brain being 10 stable but the metabolite decreasing indicate a 11 decrease in the firing rate of the receptor? 12 A. Again, the receptors don't 13 fire, it's the neuron. 14 Q. Okay. The neuron that is 15 connected to the receptor then, that the receptor 16 affects? 17 A. The neuron fire -- on a fire, 18 that depend on what impulse coming from many 19 areas of the brain, is more than just controlled 20 by the mechanism that we talked about, 21 homeostasis natural. 22 Q. Uh-huh. 23 A. So the firing of the neuron is 24 under multiple control. Page 291 1 Q. Can the neuron with the 2 serotonin receptor fire without serotonin? 3 A. I'm sorry? 4 Q. Can the neuron with the 5 serotonin receptors, can they fire without 6 serotonin? 7 A. The neuron with serotonin 8 receptor, okay. Other components may stimulate 9 its firing besides serotonin. 10 Q. Right, like we talked about 11 earlier, Dopamine, et cetera? 12 A. Right. 13 Q. But if it is connected or 14 associated with a serotonin producing cell and 15 that cell is not producing serotonin and no other 16 neurotransmitters happen to come by, is it going 17 to fire? 18 A. So you are talking about a 19 situation that the cell facing the serotonin 20 neuron have no other neuron have input? 21 Q. Input of neurotransmitters, 22 right. 23 A. So when there is only 24 serotonin have an input -- serotonin neuron have Page 292 1 an input of that neuron, then without serotonin, 2 then the neuron would not fire. 3 Q. Okay. If there is serotonin 4 in the synaptic cleft in the drawing that you 5 made earlier, okay, is there likely to be 6 Dopamine or any other neurotransmitter in there 7 also? 8 A. That synapse is mainly formed 9 by the serotonin neuron with the other neuron. 10 So that is being very specific for serotonin. 11 Q. So if something happened to 12 this cell and it stopped producing serotonin, 13 this neuron, the receptor -- with the receptor 14 illustrated in Exhibit 6, would not fire? 15 A. I suppose that would be the 16 case. 17 Q. Are you aware of any studies 18 that have compared L-tryptophan and Fluoxetine 19 for serotonin metabolite rates in spinal fluid or 20 blood in people? 21 MR. MYERS: Where those were the drugs 22 administered? 23 MS. ZETTLER: Right. 24 A. I don't recall such a study. Page 293 1 Q. You've never done a study, 2 have you? 3 A. No. 4 Q. Have you done a study like 5 that in rats? 6 A. No. 7 Q. Are you aware of any studies 8 like that being conducted at Lilly on people? 9 A. No. 10 Q. How about rats or other 11 animals? 12 A. Could you repeat that question 13 again, please? 14 Q. Sure. Where you have a study 15 where a group of either rats or humans are placed 16 on L-tryptophan and another group is given 17 Fluoxetine and the serotonin metabolite level is 18 measured, either in the -- 19 A. Compare Fluoxetine with 20 tryptophan? 21 Q. Right. 22 A. I'm not aware of such study 23 being done. 24 MS. ZETTLER: Let's take a quick Page 294 1 break. 2 (A SHORT RECESS WAS TAKEN.) 3 Q. (BY MS. ZETTLER) Other than 4 inhibiting the uptake or reuptake of serotonin, 5 does Fluoxetine have any effect on the receptors 6 themselves, directly? 7 A. I understand, yes. It has 8 very, very weak interaction with receptors of 9 other neurotransmitters so far that have been 10 examined. 11 Q. You said a very weak 12 interaction? 13 A. Yes. 14 Q. With the receptors, all the 15 receptors, not just serotonin receptors. 16 A. Yes. 17 Q. What is that interaction? 18 A. Let me give a better 19 perspective. In order to interact, receptors of 20 autoneurotransmitters, you have to use 21 concentration of serotonin about three to four 22 order of magnitude higher. 23 Q. Three to four, I'm sorry? 24 A. Three or four order of Page 295 1 magnitude higher concentration in order to 2 interact with the receptors. 3 Q. So it's got to be a 4 concentration of Fluoxetine that's three or four 5 times higher than normal? 6 A. Higher than concentration 7 required to inhibit uptake of serotonin. 8 Q. Okay. 9 A. That is done in test tube. In 10 the whole animal, so far, there's no evidence 11 that Fluoxetine work on other system or receptors 12 than this ability to inhibit reuptake of 13 serotonin. 14 Q. If you are able to produce an 15 interaction between the Fluoxetine and the 16 receptor, what is the result of that interaction, 17 what happens to the receptor? 18 A. Normally when -- at those 19 concentrations, we pharmacologists consider 20 irrelevant interaction, that concentration is so 21 high, it's no longer realistic. 22 Q. Let's just -- patronize me for 23 a little bit here. What happens to the receptor 24 when you get those concentrations that high? Page 296 1 A. Most of this was done by 2 radioligand binding, there is a competing the 3 binding of the radioligand to that receptor. So 4 it's a prevent of binding of that radioligand to 5 that receptor. 6 Q. It prevents the binding of the -- 7 A. Of the radiligand -- 8 Q. To the receptor? 9 A. Yes, such as serotonin. 10 Q. Okay. 11 A. Bind to that receptor -- 12 Q. So it prevents the serotonin 13 from affecting the receptor? 14 A. Binding to that receptor at 15 the concentration three to four order magnitude 16 higher than is required to reuptake of serotonin. 17 Q. In laymen's terms, when you 18 say binding to the receptor, you mean the 19 serotonin does not have an effect on the receptor 20 then. 21 A. Yes. 22 Q. Because the Fluoxetine is 23 competing with the serotonin to bind with the 24 receptor? Page 297 1 A. Yes. 2 Q. Have any tests been done to 3 see if a similar result occurs in humans or human 4 receptors? 5 A. Yes. The radioligand binding 6 to receptor of neurontransmitters uptaken from 7 human postmortem brain tissue have been reported. 8 Q. Where? 9 A. By Doctor Richalson. 10 Q. Richardson, 11 R-I-C-H-A-R-D-S-O-N? 12 A. R-I-C-H-A-L-S-O-N. 13 Q. Richalson. Where is he 14 located? 15 A. He's located in Mayo Clinic. 16 Q. When did he publish this 17 study? 18 A. In the late '80s. 19 Q. Do you know where the study 20 was published? 21 A. I believe it was in Journal of 22 Clinical Psychiatry. 23 Q. Was that study commissioned in 24 any way by Eli Lilly? Page 298 1 A. I don't recall any 2 relationship one way or the other -- I'm sorry? 3 Q. Go ahead, I'm sorry. You 4 don't recall a relationship one way or the other? 5 A. Yes. 6 Q. Did he obtain his Fluoxetine 7 from Lilly as far as you know? 8 A. Since Lilly is the only source 9 of the Fluoxetine, yes, he must get material from 10 Lilly. 11 Q. When you do studies or tests 12 such as this, you use pure Fluoxetine, correct? 13 A. Yes. 14 Q. You wouldn't use the kind that 15 you get from a pharmacist as an average patient, 16 right? 17 A. Correct. 18 Q. The down regulation that you 19 found in your rat studies, have you ever done a 20 test testing to see if the rats eventually 21 recover from that down regulation, in other words 22 the neuron starts firing normally again? 23 A. The experiment I did was doing 24 the radioligand binding to the receptor, I didn't Page 299 1 do the firing studies, the neuron firing study. 2 I didn't do that. 3 Q. That was Doctor Fuller? 4 A. No. My work is mainly do the 5 effect of treating for animal with Fluoxetine and 6 look at the down regulation of receptors, by 7 doing the binding radioligand to the receptor, by 8 bind and grind. 9 Q. But that indicated -- your 10 results indicated a down regulation, correct? 11 A. Of a serotonin 1 receptor. 12 Q. And when you say down 13 regulation, that means the receptor was firing 14 less frequently or what is the effect of down 15 regulation on the receptor? 16 A. That receptor had been 17 activated persistently, and the receptor adapt 18 itself and no longer requires so much more 19 continuous, persistent activation for by that 20 receiving neuron, and that would be a 21 consequence. 22 Q. So it needed less serotonin to 23 activate? 24 A. The down regulation of Page 300 1 receptors is a consequence of increased 2 activation of receptor on that neuron. 3 Q. Okay. Maybe it's because it's 4 getting late, but now I'm getting confused again. 5 Would you say that one more time? Down 6 regulation -- 7 A. Down regulation is a result 8 from the persistent increased activation of that 9 receptor. 10 Q. Okay. And the increased 11 activation of the receptor is caused by the 12 continuous presence of serotonin at the receptor 13 site? 14 A. Yes. 15 Q. Okay. What happens to the 16 receptors as a result of the down regulation? 17 A. I don't know. 18 Q. Does anybody know? 19 A. Less of the receptor become 20 available. 21 Q. Less of the receptor becomes 22 available? 23 A. Yes. 24 Q. Is the portions of the Page 301 1 receptor in effect destroyed or deactivated? 2 A. The receptor just recycles 3 according to the present understanding of the 4 receptor, adaptive changes is believed that the 5 receptor would internalize within a membrane, and 6 then resurface. 7 Q. So it would regenerate itself 8 in effect? 9 A. Yes. 10 Q. But to do that, part of it 11 would have to be destroyed, correct? 12 A. Not necessarily have to be 13 destroyed. 14 Q. Would it be rendered useless? 15 A. When it's down regulated, it 16 would no longer be necessary to be in operation. 17 Q. Why? 18 A. Because this is sufficient 19 transmission taking place. 20 Q. So less of the receptor has to 21 be used for transmission? 22 A. Yes. 23 Q. So a portion of it would not 24 be used anymore? Page 302 1 A. Yes. 2 Q. Does there come a point where 3 none of the receptor is being used anymore if 4 it's activated frequently enough? 5 A. My observation have been the 6 extent of twenty-five to thirty percent of down 7 regulation never really totally render the 8 receptor totally down regulated. 9 Q. So it's twenty-five to thirty 10 percent of the receptor becomes -- down 11 regulates? 12 A. Yes. 13 Q. And then that twenty-five or 14 thirty percent is absorbed into the membrane and 15 regenerates? 16 A. It is called internalization 17 of the receptor. 18 Q. Is that twenty-five or thirty 19 percent then internalized? 20 A. That -- with Fluoxetine, I 21 don't know, I have not pursued that to 22 investigate further beyond deprevation of down 23 regulation of receptor of serotonin 1. 24 Q. Let me ask you this: If the Page 303 1 source of the continued activation of the 2 receptor that results in the down regulation is 3 removed, in other words if the continuous source 4 of serotonin at the receptor site is removed, and 5 a portion of this receptor is rendered 6 ineffective, what happens when you remove that 7 source of activation? 8 A. I have not done that type of 9 experiment with Fluoxetine, so I cannot say what 10 happened with the Fluoxetine treated condition. 11 Whether the receptor restore to the previous 12 condition, I have no knowledge one way or the 13 other. 14 Q. Does anybody? 15 A. Beg your pardon? 16 Q. Does anybody? 17 A. I try to think if that study 18 in receptors of hormone, try to address your 19 question, and I don't recall any such study being 20 done. 21 Q. I'm just interested in 22 serotonin studies, not hormone. 23 A. I don't think that have been 24 done with serotonin. Page 304 1 Q. Why didn't you study that? 2 A. I mentioned that my limit of 3 human resources. 4 Q. Don't you think that's an 5 important factor, though, if you're talking about 6 down regulation of twenty-five to thirty percent 7 of the receptor to see if that receptor 8 regenerates? 9 A. Receptor regeneration is a -- 10 technically it would be a very difficult 11 demanding research of its own, and study effect 12 of drug. 13 Q. Okay. 14 A. So it's not that I've not 15 considered this being important, it would be a 16 major research project to address the question. 17 Q. Kind of like the development 18 of Fluoxetine? 19 A. Maybe even more. 20 Q. Okay. But there's not a lot 21 of money to be made by a drug company in that 22 kind of research, is there? 23 A. I wouldn't say so. 24 MR. MYERS: Let me object to the form Page 305 1 of the question, that's an argumentative 2 question. 3 MS. ZETTLER: I think he already 4 answered it, Larry. 5 Q. How about the destruction of 6 the receptor itself by down regulation? 7 A. I think I said I don't think 8 so, that was my last comment. 9 Q. That's fine, I thought you 10 answered it. What about the destruction of the 11 receptor, the twenty-five to thirty percent of 12 the receptor that's rendered useless by down 13 regulation, did you study to see whether or not 14 that effect is reversed other than regeneration 15 once the activation stimulant is removed? 16 A. Could you repeat that? 17 Q. Sure. You testified earlier 18 that you found twenty-five to thirty percent down 19 regulation, correct? 20 A. Yes. 21 Q. And that meant that 22 twenty-five to thirty percent of the receptor was 23 rendered inoperable because of the constant 24 activation by the serotonin at the receptor site, Page 306 1 right? 2 A. Yes. 3 Q. Did you do any studies to see, 4 other than regeneration what would happen with 5 that portion of the receptor that was rendered 6 inoperable once the serotonin or constant 7 serotonin at the site was removed? 8 A. I didn't do experiment further 9 beyond what I've just mentioned, I have 10 mentioned. 11 Q. Do you know of anybody who 12 has? 13 A. I'm not aware of anybody who 14 has done such experiment. 15 Q. Have you done any experiments 16 to determine what the effect of rendering 17 twenty-five to thirty percent of the receptor 18 inoperable and then removing the Fluoxetine would 19 have on a person's ability to use serotonin, in 20 other words its effect on the receptor? 21 A. I'm not -- I don't know what -- 22 in human, I cannot comment on what happens. 23 Q. How about in rats? 24 A. In rat, after down regulation Page 307 1 of receptor, again, no overt behavioral change 2 occur. Besides measuring receptor, I also 3 monitor food intake each day. 4 Q. Intake of what? 5 A. Food intake. And Fluoxetine 6 would lower food intake, and that effect of 7 serotonergic action of Fluoxetine maintained 8 throughout the five days. 9 Q. I don't think you answered my 10 question, let me make sure that I'm communicating 11 with you because it's getting late. My question 12 is, in rats, did you do any studies to determine 13 what the effect of rendering twenty-five to 14 thirty percent of the receptor inoperable, and 15 then removing the Fluoxetine had on the 16 receptor's ability to function or the neuron's 17 ability to function? 18 A. As I mentioned earlier, I 19 didn't do those experiments. 20 Q. Do you know of anybody who 21 did? 22 A. And also I mentioned earlier, 23 I didn't know -- I don't know anybody who done 24 such experiments. Page 308 1 Q. And the reason you didn't is 2 because of the cost of human resources? 3 A. The time and human resources. 4 Q. So you don't know whether or 5 not that in effect destruction of twenty-five to 6 thirty percent of the receptor has any negative 7 effect on the transmission, the neurotransmission 8 in the serotonin neuron? 9 A. When you use the word destruct -- 10 Q. Rendering it inoperable in 11 effect destroys its ability to function, doesn't 12 it? 13 A. It's not in operation, not 14 necessarily being destroyed. 15 Q. Does it become operable again? 16 A. And that's a question that 17 have yet to be answered. 18 Q. So you don't know if it even 19 becomes operable again? 20 A. No obvious change in the 21 behavior and other responses of the animal that I 22 won't perceive that would have happened, that I 23 don't perceive what we described had happened. 24 Q. So simply because you haven't Page 309 1 noticed any overt behavioral changes in the 2 animals, then you're assuming that it has no 3 effect? 4 A. Not only no difference in 5 overt behavior, and also no change in ability to 6 suppress food intake as a measurement. 7 Q. But you also -- you said 8 yourself earlier that you are not a 9 behavioralist, correct? 10 A. Food intake measurement is not 11 necessarily behavior measurement 12 Q. But outside of food intake 13 measurement, you're not a behavioralist, correct? 14 A. You're correct. 15 Q. As far as doing your binding 16 and grinding studies and the other types of 17 studies that you have talked about earlier 18 throughout the deposition, you haven't done one 19 to determine whether or not the receptor remains 20 inoperable after the source of the down -- or the 21 cause of the down regulation is removed, right? 22 MR. MYERS: He answered that. I 23 object to the question. 24 MS. ZETTLER: He's answered if from a Page 310 1 clinical standpoint. I'm asking him as far as 2 his biochemical tests that he's performed. 3 A. I think I answered you in 4 terms of the animal studies that I have done. I 5 don't think I did answer you in a clinical 6 standpoint. 7 Q. So what's the difference 8 between the answer you just gave me about the 9 food intake and no overt behavioral -- 10 A. Those all done in rat. 11 Q. Right. I'm asking you did you 12 do any binding and grinding type studies or 13 anything like that to see whether or not there 14 was an effect with neurotransmission after down 15 regulation and the cause of the down regulation 16 was removed? 17 A. As I mentioned, no such 18 experiment had been done by myself or anybody 19 else that I'm aware of. 20 Q. Do you know what happens to 21 the serotonin metabolite in the spinal fluid of 22 human beings? 23 MR. MYERS: Let me object to the form, 24 what do you mean what happens to it? Page 311 1 MS. ZETTLER: Is it used in any way, 2 is it just there, is it absorbed into the body 3 and gotten rid of or -- 4 A. I think that's excreted into 5 the circulation. 6 Q. Are you familiar with Soloman 7 Schneider? 8 A. Yes. 9 Q. Who is Soloman Schneider? 10 A. He's a neuroscientist 11 professor at Johns Hopkins University. 12 Q. Has Doctor Schneider done any 13 work for Lilly as far as you know? 14 A. No, I don't recall. 15 Q. Have you worked with Doctor 16 Schneider? 17 A. No. 18 Q. Have you consulted with Doctor 19 Schneider? 20 A. No. 21 MS. ZETTLER: I think that's all I 22 have, Doctor. Thank you, for the education. 23 * * * * * * * * * * 24 CROSS EXAMINATION Page 312 1 BY MR. HARRIS: 2 Q. Doctor Wong, my name is Robert 3 Harris and I represent a doctor in the State of 4 Texas by the name of Noe Neaves. Are you aware 5 that Doctor Neaves has been sued? 6 A. No. 7 Q. Do you know Doctor Neaves? 8 A. I don't. 9 Q. Have you ever talked to Doctor 10 Neaves? 11 A. No. 12 Q. Do you know that he's a 13 psychiatrist? 14 A. I don't know. 15 Q. Have you ever reviewed any 16 medical records prepared by Doctor Neaves? 17 A. No. 18 Q. I take it that you are a Ph.D 19 and not an M.D. since you testified several times 20 that you're not a medical doctor? 21 A. Yes. 22 Q. So you're not familiar with 23 the standard of care that a psychiatrist 24 practicing in the State of Texas holds in Page 313 1 diagnosing and treating their patients, are you? 2 A. No. 3 Q. You don't intend to testify on 4 the standard of care in this cause or any other 5 cause, do you? 6 MR. MYERS: He doesn't. I'll 7 stipulate that he's not going to testify on the 8 standard of care. 9 Q. Have any of your findings in 10 the down regulation studies ever been published 11 in any medical journal or medical publication 12 available to medical doctors? 13 A. I mentioned that my work 14 published in the two journals, Life Science, the 15 first one, and the Journal of Neurotransmission, 16 the second one. And I don't recall any later 17 appearing in the medical journal. 18 Q. Were those published after 19 July? 20 A. I stand for correction. 21 Q. Sure, Doctor. Were any of 22 those published or were they published after July 23 of '91? 24 A. July of '91. Page 314 1 Q. If you remember. 2 A. I don't remember any of the 3 down regulation being published after 1991. 4 Q. Okay. Do you know of any 5 imperical findings or studies that suggests that 6 low levels of serotonin is a probable cause of 7 suicidal ideation or suicide in any individual or 8 human being, that is? 9 MS. ZETTLER: Other than what he 10 already testified to? 11 MR. HARRIS: I asked him as a probable 12 cause. 13 MR. MYERS: Let me object to the form 14 of the question since he's not a medical doctor. 15 MR. HARRIS: I didn't ask him that, 16 Larry. I asked him if he knew of any medical 17 finding or any imperical finding or studies that 18 suggests that it's a probable cause of suicide 19 ideation or suicide. 20 A. Would you repeat the question 21 again, please? 22 Q. Are you aware, as you sit here 23 today, of any imperical finding or study that 24 suggests or establishes that low serotonin level Page 315 1 is a probable cause of suicide ideation or 2 suicide in human beings? 3 A. That is the -- after '91, you 4 say? 5 Q. Answer that question first, if 6 you know of any, and then I'll ask you what 7 years. 8 A. I have been citing Doctor 9 Marie Asberg's publication. 10 Q. And that was published after 11 July of '91? 12 A. That was before '91. 13 Q. It was before '91. Do you 14 know approximately when? 15 A. Either '86 or '87. 16 Q. And that's the only one that 17 you know of? 18 A. Yes, that's the only one that 19 I have read. 20 Q. Was Fluoxetine mentioned in 21 that? 22 A. I beg your pardon? 23 Q. Was Fluoxetine mentioned in 24 that article, if you can remember? Page 316 1 A. I don't remember. 2 MR. HARRIS: I pass the witness. 3 * * * * * * * * * * 4 CROSS EXAMINATION 5 BY MR. SMITH: 6 Q. Doctor Wong, I'm a little 7 confused in connection with these neurons we've 8 drawn as part of your deposition that has been 9 attached as Exhibit 6. As I understand it, what 10 Exhibit 6 is is a drawing of the neurons, both 11 presynaptic and postsynaptic, in connection with 12 the neurotransmission of serotonin, is that 13 correct? 14 A. I didn't quite understand the 15 question. Would you repeat, please? 16 Q. What you've drawn here in 17 Exhibit 6 are neurons, is that right? 18 A. It's a synapse, it's a cartoon 19 depiction of a serotonin synapse. 20 Q. All right. Now what does that 21 have to do with nerves in the brain? 22 A. It is just to illustrate the 23 known biochemical event of a serotonin synapse. 24 Q. All right. My question is, do Page 317 1 you mean to imply that what you're depicting 2 there is nerve synapse or the synaptic cleft in 3 nerves? 4 A. It's a synaptic synapse. 5 Q. All right. Is a neuron and a 6 nerve the same thing as far as Exhibit 6 is 7 concerned? 8 A. Neuron deprive the nerve cell. 9 Q. All right. I guess maybe 10 that's the source of my confusion. Are you just 11 depicting in Exhibit 6 one cell of a nerve? 12 A. I only show a teeny part of a 13 serotonin nerve cell. 14 Q. Can you draw me the whole part 15 of a serotonin nerve cell? 16 A. I cannot draw you the whole 17 part of a serotonin nerve cell. 18 Q. Why? 19 A. Because I have never seen one. 20 Q. All right. Can you draw me a 21 whole part of any nerve cell regardless of 22 whether it's serotonin or Norepinephrine or 23 Dopamine? 24 A. I only can tell you the nerve Page 318 1 cell has a nucleus, have mitochondria, have 2 microsome, and I don't know how exactly to draw 3 all those nerve cell. 4 Q. Why don't you know how to draw 5 it? 6 A. I'm not a qualified cartoonist 7 to write, to draw what supposed to be like. 8 Q. Well, have you ever -- you do 9 consider yourself, as I understand it, a 10 neuropharmacologist of some sort, do you not? I 11 think we talked about that -- 12 A. I don't think I -- 13 Q. -- several months ago when I 14 questioned you earlier. 15 A. I don't think I just called 16 myself, I practice as a neuropharmacologist. 17 Q. And neuro meaning the brain or 18 the nerve system, the nervous system, isn't that 19 correct? 20 A. Yes. 21 Q. Can you not draw us some 22 depiction of a nerve in the nervous system, 23 Doctor Wong? 24 A. Drawing is not -- drawing a Page 319 1 neuron, I have not done other than the synapse of 2 what I have just drawn before, so -- 3 Q. I want to know -- you 4 attempted to depict what a synapse, a serotonin 5 synapse looks like, have you not? 6 A. That is the extent I have 7 drawn. 8 Q. All right. Now, what I want 9 you to do is depict for us and the members of the 10 jury -- you say that's just a small part of a 11 nerve? 12 A. Yes. 13 Q. Go ahead and draw us the nerve 14 in its entirety. 15 MR. MYERS: Doctor Wong, let me 16 caution you, if you're able to do so, then do so, 17 if you're not, tell Mister Smith that. You're 18 not required to do it. If you can, that's fine, 19 if you can't, tell him that. 20 A. I don't think I can draw that 21 picture for you. 22 Q. You can draw a serotonin 23 synaptic cleft, which is a part of a nerve, but 24 you can't draw a nerve, is that right? Page 320 1 A. That is already 2 over-simplified picture of a synapse. 3 Q. Whether that picture is 4 over-simplified or not, Doctor, my question 5 simply is, is it correct that you depicted the 6 presynaptic or the synaptic cleft in a serotonin 7 neuron which is a part of a nerve, and you 8 depicted that in Exhibit 6, is that correct? 9 A. Yes. 10 Q. But you cannot depict for the 11 members of the jury the nerve of which that 12 neuron and synaptic cleft looks like, is that 13 right? 14 A. That's correct. 15 Q. All right, that's fine. I'll 16 take my pen and paper back. 17 MR. MYERS: If you need to explain, go 18 ahead. 19 A. The reason why is -- 20 Q. I thought you said the reason 21 why is because you weren't a cartoonist? 22 A. No. The reason why I have 23 seen electromicroscope of a synapse, so I can 24 envision that such a picture could be drawn. Page 321 1 Whereas I have not seen an electromicrograph of a 2 whole neuron, which is probably difficult to make 3 such an electromicroscope of a whole serotonin 4 neuron. 5 Q. Doctor -- 6 MR. MYERS: Let him finish. 7 A. The reason is it's such a big 8 neuron, it's difficult to have an 9 electromicroscope to make such a drawing. You 10 can -- the artist can make imaginary picture. 11 Q. What? 12 A. An imaginary picture. But 13 having seen an electromicroscope to draw you a 14 picture is not the nature of me to draw something 15 that I haven't seen, and this I have seen many 16 times on the electromicroscope. 17 Q. Have you ever seen the 18 serotonin transporting nerve, have you ever seen 19 one? 20 A. The electromicroscopic 21 pictures, I have seen. 22 Q. I thought you had only seen 23 the synaptic cleft, which is as you -- let me 24 finish my question. Your lawyer wanted me to let Page 322 1 you finish your answer, so let me finish my 2 question. I thought you testified earlier that 3 you were having difficulty because all you had 4 seen was an electron microscope picture of the 5 synaptic cleft, and that you couldn't get the 6 whole nerve on an electron microscopic picture -- 7 microscope, is that right? 8 A. Yes. 9 Q. All right. 10 A. So what? 11 Q. So my question is, have you 12 ever been to an anatomy class or when cutting up 13 one of these rat brains, have you ever cut out a 14 serotonergic neuron or nerve or any part thereof? 15 A. No, sir. 16 Q. Can you tell the jury the 17 difference in the appearance of a brain that is 18 low in serotonin versus a brain that is high in 19 serotonin? 20 A. No, sir. 21 Q. Be it rat -- 22 A. You mean just by looking? 23 Q. Yes. 24 A. No, sir. Page 323 1 Q. Can you take a rat brain or a 2 mice brain, which it's my understanding you're 3 familiar with, is that correct? 4 A. Rat brain. 5 Q. Rat brain. Can you take a rat 6 brain and analyze a rat brain and determine 7 whether or not it has a high or low concentration 8 of serotonin within the body of that brain? 9 MR. MYERS: Let me object to the form, 10 high or low as compared to what? 11 Q. High or low as compared to any 12 normal. 13 A. The animal that we receive 14 have been well-bred animal, would consider to be 15 a normal rat. 16 Q. It would be a well-bred rat? 17 A. So I don't know what rat to 18 expect to have high or what rat you expect to 19 have low serotonin. 20 Q. I guess that's my point, 21 Doctor Wong. Is there a normal level of 22 serotonin that you expect to find in a rat's 23 brain? 24 A. Within such certain degree of Page 324 1 fluctuation of individual biological variability, 2 one can obtain a concentration of serotonin in 3 brain tissue of a rat being comparable to another 4 rat. 5 Q. All right. What is that level 6 or how do you measure it, is it point oh six 7 milligrams per kilowatt? 8 A. I don't have that number in my 9 head. 10 Q. Approximately how many rats 11 did you study or were studied under -- in 12 experiments under your direction in connection 13 with your work on Fluoxetine Hydrochloride, which 14 later became Prozac? 15 A. I'm beginning to measure 16 serotonin content in rat only last three or four 17 years. 18 Q. Why is it then your testimony, 19 Doctor Wong, that you never measured the 20 serotonin content of the brain of any rat that 21 you examined in the preclinical or experimental 22 phases that was -- that formed the data that you 23 submitted to the Food and Drug Administration to 24 secure approval for Prozac to be sold for human Page 325 1 consumption? 2 A. Doctor Fuller would be able to -- 3 Q. I'm talking about what you 4 did, Doctor. 5 A. As I said, I'm beginning to 6 measure serotonin concentration only three to 7 four years ago. 8 Q. Well, I know it's late, Doctor 9 Wong, and I'm not trying to be picky with you, 10 but I want to make sure that we know the 11 parameters within which what we're looking at. 12 A. I understand. 13 Q. And my question to you is, you 14 did a lot of experiments and compiled a lot of 15 data in connection with submitting material to 16 the Food and Drug Administration for their 17 consideration in whether or not to approve Prozac 18 for sale to humans in the United States of 19 America, correct? 20 A. Yes. 21 Q. And in any of that data or in 22 any of those experiments, did you ever measure 23 the serotonin content of any of the rats that 24 were the subject of -- rat brains that were the Page 326 1 subject of your experiments, which later formed 2 the basis of the data that was submitted to the 3 Food and Drug Administration? 4 A. I believe in 1985, one paper 5 that I published, probably that was the first 6 paper that I have in my publication showed and 7 determined serotonin content in rat. And 8 probably that was -- I should say, around that 9 time that I'm beginning to look at serotonin 10 concentration, in fact that was collaboration 11 with Doctor Fuller. 12 Q. I'm asking you what you did. 13 A. That was the initial -- 14 initiation of my measurement of serotonin. 15 Q. You first began measuring 16 serotonin in 1985 in the rat brains upon whom you 17 were experimenting? 18 A. Maybe -- in order to publish 19 the paper in 1985, I must have done -- 20 collaborated work with Doctor Fuller on that set 21 of experiments near 1984. 22 Q. All right. But the Phase 1 23 and 2 clinical trials and preclinical studies 24 were over by that time, weren't they? Page 327 1 A. Yes. 2 Q. All the toxicology studies 3 that you were doing on animals were over by that 4 time, weren't they? 5 A. Yes. 6 Q. And the conclusions that you 7 have reached with respect to Fluoxetine being an 8 inhibitor or serotonin reuptake inhibitor, had 9 already been decided before 1984 and 1985? 10 A. Yes. 11 Q. So your opinion that 12 Fluoxetine is a specific serotonin reuptake 13 inhibitor is not based on any measurements of any 14 particular amount of serotonin in any particular 15 rat brain, is that correct? 16 A. My task was to demonstrate 17 that Fluoxetine inhibited uptake of serotonin. 18 Q. I understand that. Listen to 19 my question. The court reporter is going to read 20 it for you, and I think it's subject to a yes or 21 no answer. Listen to it and see if you can 22 answer it in that way. 23 MR. MYERS: You don't have to answer 24 it yes or no. If you can, that's fine, but if Page 328 1 you need to explain it, you can. 2 (THE COURT REPORTER READ BACK THE 3 REQUESTED TESTIMONY.) 4 A. That's correct. 5 Q. All right. Because the 6 concentration of serotonin in any particular rat, 7 in any particular time, can vary, can't it, 8 Doctor Wong? 9 A. Repeat again, please. 10 Q. Because the concentration of 11 serotonin in any particular rat's brain can vary 12 at any particular time, can't it? 13 A. You refer to during the course 14 of a day? 15 Q. Yes. 16 A. Yes. 17 Q. Or the course of a week's 18 period, correct? 19 A. If one determined brain level 20 of serotonin on the same time -- between a week, 21 and you would see similar comparable levels of 22 serotonin. 23 Q. But not the same? 24 A. Would not be the same. Page 329 1 Q. Unless it was by some random 2 coincidence it happened to be the same, correct? 3 A. Within that hour, and within 4 what I mentioned earlier, the biological 5 variability of individual animals. 6 Q. Let me see if I can break it 7 down and make it a little easier. From your 8 experience and based on your judgment and 9 training and education as a biochemist, Doctor 10 Wong, do you have an opinion with respect to 11 whether or not your brain serotonin level is 12 probably different from my brain serotonin level? 13 A. I think so. 14 Q. And you think that they are a 15 different level, the two of us, as individuals, 16 have a different level of serotonin within our 17 brains as we sit here now? 18 A. I think so. 19 Q. Doctor, there are seven of us 20 sitting at this table, including Mister Myers, 21 the defense lawyer, human beings -- 22 MR. MYERS: Your question may assume 23 everyone has a brain, however. 24 A. There are seven human beings Page 330 1 with brains seated here at this table. Would it 2 be reasonable, Doctor Wong, based on your 3 training, education and experience, that probably 4 all seven of us, as we sit here today, have a 5 different serotonin level in our brain? 6 A. Our brain level would fall 7 into -- of serotonin, would fall into a cluster 8 of levels of similar -- of comparable 9 concentration. We all consider ourselves being 10 normal. 11 Q. Normal in what respect, normal 12 in that we're not mentally ill or normal in that 13 we're not physically ill? 14 A. You're not ill. 15 Q. All right. So what would be 16 that normal value, Doctor Wong? 17 A. I don't know what that normal 18 value is. 19 Q. Does anybody -- has anybody 20 ever made any determination of what the normal 21 serotonin level should be in human beings who are 22 healthy between the ages of twenty-eight and 23 fifty? 24 A. I don't have that range Page 331 1 established that I know of. 2 Q. Would it be reasonable, Doctor 3 Wong, to assume that each of us have a different 4 serotonin -- actual serotonin level now than we 5 did when we walked in the door this morning at 6 8:30 a.m.? 7 A. Our serotonin level is 8 changing during the course of a day. 9 Q. All right. 10 A. But if you measure serotonin 11 level this time tomorrow as compared with what 12 you have today, it's very comparable level that 13 you have. 14 Q. That's interesting, that's 15 interesting that each of our serotonin levels 16 varies during the day. What causes that? 17 A. That is called cycadean 18 rhythm. 19 Q. Is it your opinion then, 20 Doctor, that serotonin levels bear a relationship 21 to a cycadean rhythm? 22 A. I'm sorry, repeat again. 23 Q. Is it your opinion, then, 24 Doctor, that our serotonin levels bear a Page 332 1 relationship to cycadean rhythms? 2 A. It does have a cycadean 3 rhythm. 4 Q. And a cycadean rhythm, for the 5 jury's understanding, and mine? 6 A. It follows the hour of the 7 day. 8 Q. All right. Have there been 9 studies to determine that? 10 A. In animals. 11 Q. All right. And do you suspect 12 that that's probably accurate with respect to -- 13 that that's probably applicable to human beings? 14 A. If you allow me to 15 extrapolate, yes. 16 Q. All right. How about seasons 17 of the year, has there been any studies or any 18 research concerning whether or not the serotonin 19 levels in our brain change during seasons of the 20 year? 21 A. I'm not aware of such being 22 done. 23 Q. Are there any studies, Doctor 24 Wong, concerning whether or not during the years Page 333 1 of our lives our level of serotonin changes? 2 A. In animal study that have been 3 reported, there is some decrease in serotonin 4 concentration in the brain with age. 5 Q. With age. Does that mean that 6 those parts of the anatomy in the nerves that are 7 manufacturing serotonin are not as effective in 8 manufacturing serotonin as they were when we were 9 younger or when those rats were younger? 10 A. What causes that, I don't 11 know. 12 Q. Is this something that's just 13 being recently studied? 14 A. In recent years, yes. 15 Q. Does any of that, that is the 16 level of serotonin in our brain, have any 17 relationship to the amount of active serotonin 18 available in the synaptic cleft? 19 A. Will you please repeat for me, 20 please? 21 Q. Does any of that information 22 concerning the level of serotonin in our brain, 23 as a whole, have anything to do with the levels 24 of serotonin that are available in the synaptic Page 334 1 cleft? 2 A. Serotonin in the brain is 3 mainly localized in the neurons. 4 Q. I understand that. And there 5 is a space between the neurons, is that not 6 correct? 7 A. Yes. 8 Q. And that is the synaptic 9 cleft? 10 A. Yes. 11 Q. And in order for the serotonin 12 system to work correctly, as I understand it, 13 it's important to have the right level of 14 serotonin free in that synaptic cleft between the 15 two neurons, is that right? 16 A. Yes. 17 Q. If you didn't have any 18 serotonin as a neurotransmitter, you wouldn't get 19 any kind of serotonergic transmission, would you, 20 if you didn't have any serotonin in the synaptic 21 cleft? 22 A. I hear you. 23 Q. There's got to be that 24 substance there for the impulse to make the jump Page 335 1 from one neuron to another, isn't it? 2 A. Yes. 3 Q. Doesn't it? 4 A. Yes. 5 Q. Now, what is it that is 6 jumping? We've been talking about transmission 7 and jumping across a synaptic cleft, and things 8 of that nature. Physically, what is that that's 9 going from one neuron to another? 10 A. The molecule of serotonin. 11 Q. A molecule of serotonin. When 12 you hear the term electrical impulse, is a 13 molecule of serotonin in any way involved with 14 the electrical impulse that is measured, say, 15 like in the EEG activity of our brain? 16 A. The EEG activity of the brain 17 is summation of all the neuron's activity. 18 Q. Is the serotonin system part 19 of that? 20 A. A small part of the summation. 21 Q. If my serotonin systems were 22 not working, would it be able to be determined on 23 EEG, that's electroencephalogram? 24 A. I don't know any change have Page 336 1 been recognized. 2 Q. Do you suspect that there 3 would be some change, but that our technology is 4 not such now that it would pick that up? 5 A. As I said, the EEG is a 6 summation of millions of cells in the brain. 7 Q. But is that an electrical 8 impulse that's going like on Exhibit -- 9 MS. ZETTLER: Six. 10 Q. -- 6, the presynaptic to the 11 postsynaptic neuron, is it a piece of electricity 12 or is it simply a serotonin molecule? 13 A. The serotonin molecule have to 14 diffuse across this gap or cleft to activate as 15 receptor. 16 Q. All right. But it's a 17 molecule that's activating the receptor, not an 18 electrical charge, or does that molecule produce 19 an electrical charge? 20 A. That also could produce an 21 electrical charge as well as activate a receptor 22 would produce a biochemical event. 23 Q. When I say electrical charge, 24 I mean electricity or energy generated as a Page 337 1 result of a chemical interchange. Is that what 2 you're talking about? 3 A. Whatever the electrical charge 4 is. 5 Q. Well, I have heard it 6 described, Doctor Wong, that all of our thoughts 7 are simply electrical impulses passing through 8 our brain and from our brain down into our 9 extremities to send messages to the nerve -- to 10 the muscles and appendages, is that correct? 11 A. They're two different 12 transmission processes. One is the neurochemical 13 transmission process, which is publicated by the 14 receptor activated intracellular event to occur. 15 One other way is the receptor receive this -- 16 receive the transmission, in this case serotonin, 17 lead to publication of electrical signal. So one 18 is electrical impulse publication, and another 19 one is the neurochemical process. 20 Q. And which is involved -- in 21 what process is serotonin involved in? 22 A. Depend on which receptor. 23 Q. Is serotonin -- I'm telling 24 myself, in my brain, to move my fingers and close Page 338 1 my fist. Is serotonin involved in that process? 2 A. That is a critical question 3 that I cannot answer you, a neurological 4 question. 5 Q. My heart is beating right now, 6 and I am breathing right now. Those are 7 involuntary functions, I don't have to think 8 about that, correct, is that right? 9 A. Yes. 10 Q. Is serotonin involved in the 11 transmission of that involuntary functions of our 12 body, such as heart beat, respiration, digestion, 13 parasystolisis, and things of that nature? 14 A. Yes, it does. 15 Q. It is involved in that? 16 A. Yes, it is. 17 Q. Even to the extent that you 18 have to have transmission across these neurons 19 and across the presynaptic cleft to initiate that 20 type of transmission? 21 A. Yes, it does. 22 Q. So the serotonin system has 23 control or has an effect over body functions that 24 we have no control over, is that right? Page 339 1 MR. MYERS: Involuntary body 2 functions? 3 MR. SMITH: Yes. 4 A. Yes. 5 Q. Such as heart beat, 6 respiration? 7 A. Yes. 8 Q. Now, I don't sit and tell 9 myself to digest a meal after I eat a meal. The 10 Good Lord has made us all where we -- our brain 11 or some reaction causes our stomach to start 12 emptying in enzymes and things to begin the 13 digestive process, isn't that right, doesn't it? 14 A. Yes. 15 Q. Is the serotonin system 16 involved in digestion to some extent? 17 A. Yes. 18 Q. Is that why we see on occasion 19 that sometimes there's reports of side effects 20 with respect to Prozac of nausea? 21 A. Some literature seem to -- 22 that is the explanation. 23 Q. Because serotonin has an 24 effect on digestion, and Fluoxetine affects Page 340 1 serotonin levels and may explain the side effect 2 of nausea that we see, correct? 3 A. Yes. 4 MR. MYERS: Excuse me, Paul. Before 5 you go on, we have gone past the time I said we 6 were going to go to. Where are we? 7 MR. SMITH: We can continue Doctor 8 Wong up later if you would like. 9 MR. MYERS: No, you asked for Doctor 10 Wong for another day, and he's been here for a 11 whole another day, and I told him we were going 12 to quit at 6:00 o'clock, and he's been here two 13 full days and I think it would be appropriate to 14 wind the deposition up pretty quickly. 15 MR. SMITH: I told you at the last 16 break that I would certainly work with you in 17 connection with trying to conclude as quickly as 18 possibile because it's not my intent to keep the 19 witness here too late, but that, you know, I 20 don't want to be prohibited because you've cut it 21 off at 6:00 o'clock or 6:10, so if I have 22 additional questioning to call him back. I'm 23 trying to speed it up, but by virtue of me 24 speeding it up to try to accommodate the witness, Page 341 1 I don't want you to come in and say well, he quit 2 at 6:00, he could have gone earlier. I 3 understand you may want to object to me taking 4 his deposition for another day, and I'll wind it 5 up soon as long as you will tell me that you're 6 not going to say well, Paul quit just because he 7 wanted to, he could have kept him longer. I'm 8 quitting to accommodate you. 9 MR. MYERS: I'm going to take the 10 position that we produced him for another day and 11 we put in another full day and a little bit more, 12 and that's it. I won't take the position that 13 you quit, I'll take the position that we gave you 14 all the time you wanted. 15 MR. SMITH: As long as you understand 16 that if I quit, it's not because I feel like I've 17 had all I've wanted. 18 MR. MYERS: That's fine. I told the 19 witness we were going to stop. 20 MR. SMITH: Give me five more minutes 21 and hopefully I can complete this, at least, 22 train of thought. 23 MR. MYERS: Five more minutes. 24 Q. I'm trying to hurry, Doctor Page 342 1 Wong. When we get scared or get angry, our body -- 2 you as a biochemist know that our body has 3 various biochemical reactions, doesn't it? 4 A. I believe so. 5 Q. Such as heart may start 6 beating faster? 7 A. Yes. 8 Q. Then may be a release of a 9 particular hormone that cause us to react quicker 10 if we're afraid? 11 A. Yes. 12 Q. We maybe start perspiring? 13 A. Yes. 14 Q. And we may become nervous or 15 agitated? 16 A. Yes. 17 Q. Does the serotonin system 18 affect those involuntary responses that we have? 19 A. This -- again, I only familiar 20 with animal studies. When animal is under 21 stress, it will affect serotonin as well as other 22 neurotransmitters. 23 Q. All right. So the serotonin 24 system is involved in our reactions to stress? Page 343 1 A. Yes. 2 Q. Would that explain some of the 3 side effects that had been reported with respect 4 to Prozac, such as increased anxiety and 5 nervousness, the fact that the serotonin system 6 is involved in some of these natural involuntary 7 responses that we have to stress? 8 MR. MYERS: I object to the question 9 only to the extent it may call upon him to render 10 some medical opinion. But if you know, tell him. 11 A. I don't feel qualified to 12 address the -- to answer the question, because I 13 can only mention what I know about studying 14 animal. 15 Q. You were able to answer it 16 with respect to nausea, correct? 17 A. That is what the literature 18 explained. 19 Q. That nausea -- 20 A. Yes, have to do with the 21 serotonin. 22 Q. All right. And doesn't the 23 literature explain that increased anxiety and 24 nervousness, as side effects to Fluoxetine, are Page 344 1 the result of the fact that Fluoxetine affects 2 the serotonin system? It's as simple as that. 3 A. I have yet to -- I have not 4 come across that kind of literature, that kind of 5 interpretation. 6 Q. Have you ever looked at a 7 package insert with respect to Fluoxetine? 8 A. I have not. 9 Q. What was that? 10 A. I have not. 11 Q. I thought you had some input 12 in connection with the package insert? 13 A. In the preclinical 14 pharmacology segment. 15 Q. And you went to the Food and 16 Drug Administration and explained why a flu-like 17 symptom with another antidepressant, that's a 18 specific serotonin reuptake inhibitor, might be a 19 causative factor, correct? 20 A. Yes. 21 Q. You felt qualified to explain 22 to the Food and Drug Administration those 23 factors, didn't you, is that right? 24 A. I need to mention that that Page 345 1 was interpretation of the chemist from Astra, a 2 chemist's interpretation of the flu-like 3 syndrome. 4 Q. I believe you told us that the 5 chemical explanation that you offered to the 6 members of the advisory committee at the Food and 7 Drug Administration was by virtue of the chemical 8 structure of that particular antidepressant, 9 Zimelidine, that you thought that the very fact 10 that it had a particular chemical structure, it 11 could account for those flu-like symptoms, 12 correct? 13 A. That is -- first of all, that 14 was an interpretation that the chemist of Astra 15 provide, and also -- 16 Q. You didn't disagree with that 17 interpretation, did you? 18 MR. MYERS: Let him finish. 19 A. Let me finish. It's known, 20 the reason why that molecule being -- I explained 21 the way I did was that molecule have the 22 propensity to form a coalliant bond to protein, 23 which I have so happened to have read publication 24 that a conjugated protein would produce immuno Page 346 1 response. 2 Q. And the flu-like symptoms? 3 A. That was animal study that was 4 reported, and with the chemist from Astra's 5 explanation, and I considered that being 6 consistent. 7 Q. So it was your experience and 8 your opinion that you expressed to the Food and 9 Drug Administration that that syndrome was by 10 virtue of the particular chemical structure of 11 that particular antidepressant, correct? 12 A. Yes. 13 Q. And you were explaining to the 14 Food and Drug Administration advisory committee 15 that you as a biochemist, familiar with 16 Fluoxetine, helped in the development of 17 Fluoxetine, that Fluoxetine had a different 18 chemical structure, correct? 19 A. Yes. 20 Q. And that by virtue of the fact 21 that it had a different chemical structure, it 22 would have a different biological response from 23 that produced by Zimelidine, which had another 24 chemical structure, correct? Page 347 1 A. Yes. 2 Q. And so you were able to give a 3 biological reason for a physical -- I mean a 4 biochemical reason for a physical difference in 5 human beings between those two antidepressants, 6 correct? 7 A. The explanation I provide 8 seemed to be accepted by the advisory committee. 9 Q. I understand that, and I'm not 10 quarreling with that opinion that you've 11 expressed to them, Doctor, I don't have any 12 judgment on that one way or the other. My point 13 is or my question to you is, so I make sure I 14 understand, that opinion you were giving was that 15 you knew or you could opinion, based on your 16 expertise as a biochemist and one familiar with 17 these structures, that simply by virtue of the 18 fact that these two chemicals had a different 19 molecular chemical make-up, that one would 20 produce a particular response and another 21 wouldn't, isn't that correct? 22 MR. MYERS: I object to the form. 23 That doesn't include all the other things he said 24 he took into consideration, and once he answers Page 348 1 the question, we're through for the day, okay, 2 we're done past the five minutes. But if you 3 know the answer to the question, tell Mister 4 Smith, or if you want the court reporter to read 5 it back. 6 A. Again, I lost that -- go ahead 7 and read it back. 8 (THE COURT REPORTER READ BACK THE 9 REQUESTED TESTIMONY.) 10 A. I don't know what is correct 11 or not correct. 12 Q. All right. Even though you 13 said that's my last question, can I rephrase that 14 question? 15 MR. MYERS: Rephrase that question. 16 Q. Your explanation was that the 17 two chemicals produced different physical 18 conditions by virtue of their different chemical 19 make-ups? 20 A. Yes. 21 MR. SMITH: I'm not finished with my 22 questions, Counsel. 23 MR. MYERS: Well, we can provide the 24 witness if we had another day, we can debate that Page 349 1 outside the presence of the witness. I just ask 2 that the court reporter note the time, it's 6:20 3 that we're concluding on the record, and I want 4 the record to reflect that. 5 MS. ZETTLER: Plus the fact that we 6 have not seen errata sheets from the first 7 portion of Doctor Wong's deposition. 8 MR. MYERS: I would take that up with 9 the court reporter that took the deposition. 10 MS. ZETTLER: We may have questions 11 based on the changes he made in the deposition. 12 Part of the problem, as you know, Larry, is that 13 it just takes so long to produce things prior to 14 the confidentiality statement. 15 MR. SMITH: Doctor Wong, thank you. 16 MR. MYERS: No questions. 17 (THE WITNESS WAS EXCUSED.) Page 350 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. DAVID T. WONG 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 12TH DAY OF 19 MAY, 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 351 1 E R R A T A S H E E T 2 3 COMMONWEALTH OF KENTUCKY ) : SS 4 COUNTY OF JEFFERSON ) 5 6 I, DR. DAVID T. WONG, THE UNDERSIGNED 7 DEPONENT, HAVE THIS DATE READ THE FOREGOING PAGES 8 OF MY DEPOSITION AND WITH THE CHANGES NOTED 9 BELOW, IF ANY, THESE PAGES CONSTITUTE A TRUE AND 10 ACCURATE TRANSCRIPTION OF MY DEPOSITION GIVEN ON 11 THE 13TH DAY OF APRIL, 1994 AT THE TIME AND PLACE 12 STATED THEREIN. 13 PAGE NO. LINE NO. CHANGE REASON Page 352 1 2 PAGE NO. LINE NO. CHANGE REASON 3 4 5 6 7 8 9 _____________________________ 10 DR. DAVID T. WONG 11 SWORN TO AND SUBSCRIBED BEFORE ME THIS 12 _____ DAY OF __________, 1994. 13 _____________________________ NOTARY PUBLIC, STATE OF 14 KENTUCKY AT LARGE Page 353 1 2 3 4 5 6 7 8 9 Page 354 1 DIRECT EXAMINATIONBY MS. ZETTLER:.................14 2 CROSS EXAMINATIONBY MR. HARRIS: .................300 3 CROSS EXAMINATIONBY MR. SMITH:...................304 4 COMMONWEALTH.....................................338 5 PLAINTIFFS' EXHIBIT NO. 1.........................29 6 PLAINTIFFS' EXHIBIT NO. 2.........................36 7 PLAINTIFFS' EXHIBIT NO. 3.........................55 8 PLAINTIFFS' EXHIBIT NUMBER 4......................79 9 PLAINTIFFS' EXHIBIT NO. 5.........................90 10 PLAINTIFFS' EXHIBIT NUMBER 6.....................170 11 PLAINTIFFS' EXHIBIT NO. 7........................223 12 13 14 15 16 17 18 Page 355 1 DIRECT EXAMINATIONBY MS. ZETTLER:.................15 2 CROSS EXAMINATIONBY MR. HARRIS: .................313 3 CROSS EXAMINATIONBY MR. SMITH:...................317 4 COMMONWEALTH.....................................351 5 PLAINTIFFS' EXHIBIT NO. 1.........................30 6 PLAINTIFFS' EXHIBIT NO. 2.........................37 7 PLAINTIFFS' EXHIBIT NO. 3.........................56 8 PLAINTIFFS' EXHIBIT NUMBER 4......................82 9 PLAINTIFFS' EXHIBIT NO. 5.........................94 10 PLAINTIFFS' EXHIBIT NUMBER 6.....................177 11 PLAINTIFFS' EXHIBIT NO. 7........................232 12 13 14 15 16 17 18 Page 356