1631 1 IN THE UNITED STATES DISTRICT COURT 2 DISTRICT OF WYOMING 3 -------------------------------------------------------- 4 THE ESTATES OF DEBORAH MARIE TOBIN and ALYSSA ANN TOBIN, deceased, by 5 TIMOTHY JOHN TOBIN, personal representative; and THE ESTATES OF 6 DONALD JACK SCHELL and RITA CHARLOTTE SCHELL, deceased, 7 by NEVA KAY HARDY, personal representative, 8 Plaintiffs, Case No. 00-CV-0025-BEA 9 vs. June 1, 2001 Volume IX 10 SMITHKLINE BEECHAM PHARMACEUTICALS, 11 Defendant. ----------------------------------------------------------- 12 13 14 TRANSCRIPT OF TRIAL PROCEEDINGS 15 16 Transcript of Trial Proceedings in the above-entitled 17 matter before the Honorable William C. Beaman, Magistrate, 18 and a jury of eight, at Cheyenne, Wyoming, commencing on the 19 21st day of May, 2001. 20 21 22 23 Court Reporter: Ms. Janet Dew-Harris, RPR, FCRR Official Court Reporter 24 2120 Capitol Avenue Room 2228 25 Cheyenne, Wyoming 82001 (307) 635-3884 1632 1 A P P E A R A N C E S 2 For the Plaintiffs: MR. JAMES E. FITZGERALD Attorney at Law 3 THE FITZGERALD LAW FIRM 2108 Warren Avenue 4 Cheyenne, Wyoming 82001 5 MR. ANDY VICKERY Attorney at Law 6 VICKERY & WALDNER, LLP 2929 Allen Parkway 7 Suite 2410 Houston, Texas 77019 8 For the Defendant: MR. THOMAS G. GORMAN 9 MS. MISHA E. WESTBY Attorneys at Law 10 HIRST & APPLEGATE, P.C. 1720 Carey Avenue 11 Suite 200 Cheyenne, Wyoming 82001 12 MR. CHARLES F. PREUSS 13 MR. VERN ZVOLEFF Attorneys at Law 14 PREUSS SHANAGHER ZVOLEFF & ZIMMER 225 Bush Street 15 15th Floor San Francisco, California 94104 16 MS. TAMAR P. HALPERN, Ph.D. 17 Attorney at Law PHILLIPS LYTLE HITCHCOCK 18 BLAINE & HUBER, LLP 3400 HSBC Center 19 Buffalo, New York 14203 20 INDEX TO WITNESSES DEFENDANT'S PAGE 21 J. JOHN MANN Continued Cross - Mr. Vickery 1634/1731 22 Redirect - Mr. Preuss 1753 23 DEE POWERS Direct - Mr. Gorman 1706 24 Cross - Mr. Fitzgerald 1730 25 1633 1 INDEX TO WITNESSES CONTINUED 2 DEFENDANT'S PAGE ARTHUR MERRELL, M.D. 3 Direct - Mr. Gorman 1757 4 INDEX TO EXHIBITS PLAINTIFF'S RECEIVED 5 62 1676 6 DEFENDANT'S SB-LL 1672 7 SB-MM 1673 SB-NN 1673 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 1634 09:32:52 1 P R O C E E D I N G S 09:32:52 2 (Trial proceedings reconvened 09:32:52 3 9:30 a.m., June 1, 2001.) 09:33:12 4 THE COURT: Dr. Mann, I presume you recall you're 09:33:14 5 still under oath? 09:33:16 6 THE WITNESS: Yes, I do, Your Honor. 09:33:17 7 THE COURT: Mr. Vickery, you may proceed. 09:33:21 8 MR. VICKERY: Thank you, Your Honor. 9 10 J. JOHN MANN, M.D., 11 called as a witness on behalf of the Defendant, being 12 previously duly sworn, testified further as follows: 13 CONTINUED CROSS-EXAMINATION 09:33:23 14 Q. (BY MR. VICKERY) Good morning, sir. 09:33:25 15 A. Good morning. 09:33:28 16 Q. In the ACNP paper which is Joint Exhibit 245, I believe, 09:33:33 17 for our record, you referenced the fact that some unpublished 09:33:39 18 data from SmithKline Beecham had been provided to your task 09:33:43 19 force, correct? 09:33:44 20 A. Yes. 09:33:45 21 Q. And let's just look at the paragraph -- I have it up on 09:33:48 22 the board here -- and read it together. We will save our 09:33:55 23 voices. Would you like to read or me? 09:33:58 24 A. "Data supplied by the manufacturer of paroxetine indicate 09:34:04 25 that in a population of 4,668, patients were randomized to 1635 09:34:09 1 either paroxetine, 2963; placebo, 544; or other active 09:34:15 2 antidepressants, 1,151, for a six-week double-blind control 09:34:21 3 clinical trial and in some cases follow-up continuation 09:34:26 4 pharmacotherapy or maintenance treatment studies. There were 09:34:30 5 five suicides in the paroxetine group, two in the placebo 09:34:34 6 group and three in the other active treatments group." 09:34:39 7 Q. Let me stop you at the end of that sentence. I'm confused 09:34:43 8 and I'm sure you can straighten us out on this. When it says 09:34:46 9 randomized, there are 4,468 patients and they're randomized 09:34:53 10 by two-thirds get paroxetine, 2963, can you explain that for 09:34:59 11 me? 09:35:00 12 A. Well, these were actually a series of different studies 09:35:09 13 and it is not uncommon practice to sometimes have more 09:35:16 14 patients getting the drug you're testing than getting the 09:35:21 15 placebo or the comparison drug. 09:35:25 16 And the reason that's done is so that you can get 09:35:28 17 additional information on the safety and the efficacy of the 09:35:35 18 drug that you're testing because you already have a fair idea 09:35:38 19 what the safety and efficacy of the drug you're comparing it 09:35:42 20 to because those drugs have usually been around for a long 09:35:45 21 time. And since this is a new drug and you want to learn as 09:35:48 22 much about it as you can, it is not uncommon to have more 09:35:52 23 patients on that drug than the comparators. 09:35:55 24 Q. Thank you. We've heard a lot about placebo controls in 09:35:58 25 this trial already, particularly from Dr. Wang on Monday. 1636 09:36:03 1 Would you agree, at least insofar as you're trying to 09:36:06 2 have some control group, that in this case we have almost six 09:36:09 3 times -- a little over five times, I guess, as many people on 09:36:15 4 paroxetine as in the placebo control arm? 09:36:18 5 A. Yes. That's also not uncommon because the -- the reason 09:36:25 6 is that we try to treat as few people as possible with 09:36:29 7 placebo as we can in order to reduce the burden that we're 09:36:36 8 placing on people in participating in these studies. Most 09:36:41 9 people go into the studies hoping to be on the active drug so 09:36:44 10 we try to weight the odds so that they are on the active 09:36:47 11 drug, and they usually go on an active drug after they finish 09:36:50 12 the placebo period. But that's very common to have the 09:36:53 13 fewest number on placebo as possible. 09:36:56 14 Q. Dr. Mann, let me ask you this. I know there were four 09:36:58 15 members of your task force. Did you have access to all of 09:37:02 16 the data, all of the unpublished data, or were you provided 09:37:06 17 with summaries or statistical summaries of the data from 09:37:12 18 SmithKline? 09:37:14 19 A. To be perfectly honest, I can't recall how much of the 09:37:22 20 statistical raw data we received at the time that we put 09:37:26 21 these numbers together. 09:37:27 22 Q. Is it possible that you just had statistical summaries 09:37:30 23 from SmithKline? 09:37:31 24 A. It is conceivable that we got summary tables like the kind 09:37:36 25 from which these data were abstracted. That would be very 1637 09:37:40 1 different than to say the results -- the way Dr. Kahn did his 09:37:48 2 study where I think he basically got comparable results where 09:37:52 3 he actually went to the FDA database and looked at all of the 09:37:56 4 raw data. 09:37:57 5 Q. Okay. Now, did you personally review this data on 09:38:00 6 paroxetine back at the time the task force was working or did 09:38:04 7 one of the other members of your task force do that? 09:38:53 8 A. No, I think we all went through the tables of data that 09:38:53 9 were provided at the time. 09:38:53 10 Q. All right. Let's read on here for a minute and then we'll 09:38:53 11 come back to some other things to talk about. 09:38:53 12 Let me do the next one. 09:38:53 13 "When these data are converted to suicides per 09:38:53 14 patient exposure year, the number of suicides per patient 09:38:53 15 exposure year was .005 in the paroxetine group, .028 in the 09:38:53 16 placebo group and .014 in the active control treatment 09:38:53 17 group." 09:38:53 18 Question: Who made the decision to convert the data 09:38:53 19 to patient exposure years? 09:38:57 20 A. Well, we've reported the data here both ways, but the 09:38:57 21 reason that one is actually -- must present the data in this 09:39:04 22 way, patient exposure years, is that in some studies patients 09:39:07 23 were on the medication for four weeks or six weeks. In other 09:39:10 24 cases the patients were on the medication for months. 09:39:16 25 So the people who were on any particular medication, 1638 09:39:19 1 be it Paxil or a tricyclic, a TCA, or a placebo who were on 09:39:27 2 it for four or six weeks, were only on the medication a short 09:39:30 3 time. The people on it for six months were on it for a much 09:39:34 4 longer time. If you think there's an adverse event that 09:39:37 5 you're looking for or a beneficial effect that you're looking 09:39:40 6 for, you want to see how long the patient has been on the 09:39:43 7 medication because it is not an equal playing field if the 09:39:47 8 patient has only been on the meds for six weeks versus six 09:39:52 9 months. It is not an equal playing field if you're trying to 09:39:56 10 see if it is doing any good and it is not an equal playing 09:39:59 11 field if you're trying to see if the medication is doing any 09:40:02 12 harm. 09:40:02 13 So by converting it to a standard unit, patient 09:40:05 14 exposure years, you get an equivalence in terms of the 09:40:09 15 exposure of the patient to the particular medication. 09:40:14 16 Q. You're very familiar both from his written reports and 09:40:17 17 from his deposition testimony with the position of Dr. Healy 09:40:20 18 regarding this issue, aren't you? 09:40:27 19 A. I have some familiarity. I wouldn't say very familiar. 09:40:29 20 Q. What you know, don't you, is that he says that for that 09:40:32 21 group of people we were discussing yesterday, the small 09:40:36 22 minority of vulnerable people, that the danger period is in 09:40:39 23 the first week, two weeks, maybe the first month, in other 09:40:42 24 words, in the early part of taking the drug. 09:40:45 25 You understand that's his view, don't you? 1639 09:40:48 1 A. I'm sure you know his view better than I do, and if you 09:40:52 2 say so, then let's assume that's the case. 09:40:56 3 Q. All right. Well, Dr. Wang explained to us on Monday that 09:40:59 4 when you convert it to patient exposure years that you're 09:41:03 5 really weighting the experience of the person that was on for 09:41:06 6 a whole year for whom it worked just fine basically 52 times 09:41:13 7 heavier than the guy that was just on it one week and had a 09:41:16 8 real bad experience. 09:41:17 9 That's true, isn't it? 09:41:19 10 A. That's why it is useful to see the data presented in more 09:41:24 11 than one type of fashion. But the fact of the matter is that 09:41:31 12 that doesn't tell the whole story the way you've described 09:41:34 13 it. 09:41:35 14 Let's assume -- 09:41:37 15 Q. Excuse me. If we can, let's proceed on questions and 09:41:40 16 answers, okay? 09:41:41 17 A. Okay. 09:41:42 18 Q. Now, the -- the way that you chose to present the data in 09:41:47 19 the ACNP paper was in terms of patient exposure years, right? 09:41:52 20 A. That's correct. 09:41:52 21 Q. And are you the person that made the decision to weight it 09:41:55 22 and portray it in that fashion or did someone else on your 09:41:59 23 task force make that recommendation? 09:42:02 24 A. The entire content of the paper represents a consensus 09:42:05 25 statement. I was one of the people that had input into that. 1640 09:42:10 1 Q. All right. Now, let's read on. 09:42:15 2 "There were no statistically significant differences 09:42:18 3 across the three treatment groups. With regard to attempted 09:42:21 4 suicides, there were also no significant differences among 09:42:24 5 the three groups. The number of suicide attempts per patient 09:42:28 6 exposure year was 0.40 in the paroxetine group, 0." -- is 09:42:38 7 that an 83 in the placebo group? 09:42:40 8 A. Yes. 09:42:42 9 Q. -- "and 0.55 in the other active treatment groups." 09:42:48 10 Now, the suicide attempts are actually just in terms 09:42:51 11 of the raw data much higher? 09:42:53 12 A. Yes. Could I interrupt you there because I'm glad you 09:42:56 13 mentioned that. I'm sure you've noticed this, actually, but 09:43:01 14 it is important that others be aware of this -- 09:43:03 15 Q. Excuse me, Doctor. 09:43:05 16 THE COURT: Let's let him finish. We're not going to 09:43:07 17 interrupt the witness. Let him finish his statement. 09:43:12 18 A. You asked about the attempted suicide. That number, 09:43:16 19 that's a typographical error, I'm sure you know that. 09:43:20 20 Q. (BY MR. VICKERY) I didn't know that. 09:43:21 21 A. Well, if you look at the Montgomery paper which reviewed 09:43:24 22 the data in much greater detail, you will see that the 09:43:28 23 numbers are all identical except for the number that relates 09:43:33 24 to the suicide attempt number. That .40 should be .04. 09:43:46 25 Q. I didn't know that. I appreciate your telling me. 1641 09:43:52 1 Now we're going to go look at those 2963 patients in 09:43:57 2 a minute, but before we do that there's another statement 09:44:00 3 that I want to ask you about. 09:44:02 4 "Even if the FDA spontaneous reporting system were to 09:44:06 5 pick up only 1 out of every 100 instances" -- I know why the 09:44:11 6 rest of the sentence is there, but I want to ask you about 09:44:14 7 the first part of the sentence. 09:44:16 8 Why did you write down the FDA might only pick up 1 09:44:19 9 out of 100 instances? 09:44:23 10 A. Okay, that's unrelated to the paroxetine data paragraph. 09:44:29 11 Of course that's referring to the previous paragraph which 09:44:32 12 talks about Prozac. 09:44:33 13 Q. Isn't it talking about the effectiveness of the FDA's 09:44:37 14 spontaneous reporting system to pick up adverse events? 09:44:41 15 A. Yes. I just wanted to clarify that that is completely 09:44:44 16 unrelated to the paroxetine data we just discussed. 09:44:51 17 The FDA reporting system is an effort to try and 09:44:54 18 track reports of serious adverse unexpected kinds of events 09:45:03 19 that occur with medication, and I'm sure you've heard from 09:45:07 20 Dr. Wang and Dr. Wheadon on this, but the rate of report -- 09:45:12 21 reporting of such adverse events depends heavily on a lot of 09:45:17 22 things, for example, how serious the problem is; how much 09:45:24 23 publicity the problem may have received in the literature and 09:45:28 24 so on, in other words, how aware doctors are of this. 09:45:34 25 So we took a number, 1 in every 100 events as the 1642 09:45:40 1 most extreme, conservative underreporting of an event. So 09:45:45 2 our assumption is that the event -- the number of reports was 09:45:51 3 actually much likely more frequent than 1 in every 100, at 09:46:00 4 least what doctors were seeing, but we wanted to take it to 09:46:03 5 an extreme so that nobody would quarrel with the conclusion 09:46:05 6 we were discussing in the previous paragraph. But since you 09:46:08 7 don't know what is in the previous paragraph, this becomes a 09:46:12 8 bit theoretical. 09:46:13 9 Q. Well, they will have it. The jury will have it to read. 09:46:16 10 The reason, kind of bottom line, that you put that in 09:46:19 11 there is that you recognize that there is significant 09:46:22 12 underreporting of adverse events to the FDA, right? 09:46:29 13 A. Yes, we recognize there is underreporting and we were 09:46:33 14 taking that into account in drawing conclusions about a 09:46:36 15 lower-than-one-would-predict suicide rate on Prozac even 09:46:41 16 though it was prescribed to depressed patients. 09:46:53 17 Q. Let's look at the 2964 people, if we may, and first we'll 09:46:56 18 look at the first page of the exhibit. This is Plaintiff's 09:46:59 19 Exhibit 12, for the record, and this is the compilation of 09:47:05 20 data that was submitted in support of the new drug 09:47:09 21 application for paroxetine. 09:47:11 22 This is the same data that was available to you, 09:47:14 23 isn't it, or do you know? 09:47:23 24 A. You mean for the purpose of preparing this paper? I don't 09:47:29 25 know. 1643 09:47:29 1 Q. Okay. If it turns out that there are 2963 patients on 09:47:35 2 paroxetine in this document, would you think that's probably 09:47:38 3 the exact same database that you were looking at when you 09:47:41 4 wrote the task force paper? 09:47:42 5 A. I think if the numbers match in the three treatment 09:47:46 6 groups, that sounds like a reasonable assumption. 09:47:49 7 Q. Okay. Now, the date, of course, that this was submitted 09:47:52 8 was November 1989, and we all know by now that was about 09:47:58 9 three months before the Teicher and Cole article brought the 09:48:03 10 concerns about suicide into the public consciousness, 09:48:07 11 correct? 09:48:20 12 A. 1989 was earlier, yes. 09:48:35 13 Q. Dr. Mann, in this exhibit there are some tables of adverse 09:48:38 14 experiences which occurred during active treatment. In this 09:48:41 15 particular table, V-1, it is in the non-U.S. phase II and III 09:48:50 16 studies. 09:48:51 17 And do you see how they're categorized -- let me zoom 09:48:55 18 out a bit first -- that they're categorized in several ways, 09:49:01 19 first by preferred term -- 09:49:03 20 A. I'm not sure if this matters or not, but now I can't see 09:49:08 21 it at all. I don't know if the jury can see it, but I 09:49:11 22 certainly can't. 09:49:12 23 Q. Let me zoom in just a little bit, then. 09:49:22 24 A. Bigger would be better. 09:49:24 25 Q. I'll zoom in in a second. I'm trying to show the 1644 09:49:27 1 different field, okay? 09:49:29 2 A. Sure. 09:49:29 3 Q. You see there's first a preferred term, then there's a 09:49:32 4 treatment paragraph which tells us if this person is on the 09:49:35 5 placebo or the control group or whether they're on 09:49:39 6 paroxetine. 09:49:42 7 Have you seen this kind of presentation of data 09:49:44 8 before? 09:49:45 9 A. Question is have I seen this before? 09:49:51 10 Q. This type of presentation of data where this is the kind 09:49:51 11 of information presented in data fields? 09:49:59 12 A. Can we go over that again? 09:50:00 13 Q. Yes, sir. Have you seen this kind of a database presented 09:50:06 14 before to show information about a patient's adverse 09:50:10 15 experiences on a drug? 09:50:13 16 A. Yes, I have. Can you make it bigger? 09:50:17 17 Q. Yes, I will make it bigger. 09:50:19 18 A. Thanks, that's much better. 09:50:22 19 Q. And we will zoom left or right -- 09:50:26 20 A. No, it was fine before. 09:50:28 21 Q. So we have the treatment, then we have a patient 09:50:30 22 identifier, right? 09:50:32 23 A. Uh-huh. 09:50:33 24 Q. You need a verbal answer, please, sir, for our record. 09:50:36 25 A. Yes. 1645 09:50:36 1 Q. And then we have an age? 09:50:40 2 A. Uh-huh. 09:50:41 3 Q. Correct? 09:50:41 4 A. Yes. 09:50:41 5 Q. And then the sex? 09:50:42 6 A. Yes. 09:50:43 7 Q. Then we have the term that the investigator used to 09:50:47 8 describe the event, correct? 09:50:50 9 A. Yes. 09:50:52 10 Q. Then we have the date of onset, how long they had been on 09:50:56 11 the drug before this started, correct? Is that correct, sir? 09:51:02 12 A. I assume that's what that represents, onset, yes. 09:51:06 13 Q. And then we show the dose that they're on, right? 09:51:10 14 A. Right. 09:51:17 15 Q. And then we show when they stopped the drug, correct? 09:51:22 16 A. Right. 09:51:22 17 Q. Then we show the drug relatedness, true? 09:51:30 18 A. I assume that -- I don't know. It says drug relate, 09:51:34 19 right. 09:51:35 20 Q. Let's look down at the bottom and see what that means. Do 09:51:51 21 you see along the bottom where the people determining if this 09:51:53 22 is related to the drug have five different choices? They can 09:51:56 23 say either this is definitely not related, that's a 1, or it 09:52:02 24 is probably not, possibly it is related, it is probably 09:52:05 25 related or it is definitely related to the drug; you see 1646 09:52:09 1 where they can make those choices? 09:52:13 2 A. Yes, I see the scale. 09:52:15 3 Q. Let's go back up and see what they decided with respect to 09:52:19 4 this first one here. This is a 46-year-old male who 09:52:27 5 attempted suicide on day 18, correct, sir, the first entry? 09:52:34 6 A. Yep. 09:52:36 7 Q. And what did SmithKline Beecham indicate was its 09:52:38 8 relatedness to the drug? 09:52:40 9 A. Well, I'm not sure who completed these forms and who made 09:52:44 10 these estimations. 09:52:47 11 Q. Didn't I just show you the cover sheet that said it was 09:52:50 12 Beecham Laboratories? 09:52:52 13 A. Said Beecham Laboratories, said it was a report. I don't 09:52:55 14 know who made the ratings. How can you tell? 09:52:58 15 Q. Whoever made this report, did they decide that it was 09:53:01 16 definitely related to the drug? 09:53:03 17 A. They gave it a 5, sure. I don't know who that is, though. 09:53:07 18 Q. How about the next one, 23-year-old female attempted 09:53:10 19 suicide on day 11, was that a 5? 09:53:13 20 A. Sure, I see that. 09:53:15 21 Q. Look down here halfway through -- and I don't know if my 09:53:20 22 highlight shows up on your screen. 09:53:23 23 A. It does. 09:53:23 24 Q. See this 61-year-old female that made a suicide attempt on 09:53:27 25 day 1 of the drug, and what did they say there? 1647 09:53:33 1 A. Score is a 3. 09:53:36 2 Q. Possibly. There's a 63-year-old male that had suicide 09:54:10 3 ideation. He had been on it 42 days but did they say that 09:54:10 4 was definitely related to the drug? 09:54:10 5 A. That's what the table says. 09:54:10 6 Q. And down here, a 21-year-old female on day 17, suicide 09:54:11 7 attempt, definitely related to the drug? 09:54:15 8 A. That's what it indicates. 09:54:18 9 Q. We can go on and on with this, but were you provided with 09:54:21 10 this information in 1991? 09:54:26 11 A. As you can see from the previous discussion, my 09:54:31 12 recollection is we were given the summary tables that 09:54:36 13 provided the data that went into this paper. 09:54:48 14 Q. Were you given summary tables like this one where the 09:54:52 15 2,963 patients were on paroxetine and 2 of them had delusions 09:54:58 16 but it was just rounded down to zero percent? Is that the 09:55:03 17 kind of summary tables that were provided to your task force? 09:55:18 18 THE COURT: What exhibit is that? 09:55:20 19 MR. VICKERY: It is all a part of 12, Your Honor. 09:55:22 20 THE COURT: All right. 09:55:23 21 A. You may recall -- it is difficult to say exactly what the 09:55:30 22 format and content of these tables were. We had data from -- 09:55:34 23 I think from the top of my head, for at least four different 09:55:40 24 compounds. Each company had its own way of laying out the 09:55:44 25 data and presenting the data. 1648 09:55:48 1 I don't have access to the original material that was 09:55:50 2 provided for this particular paper, so if I were to say, it 09:55:54 3 would have to be a guess, so I don't know. 09:55:57 4 But if there's a particular point about this table 09:55:59 5 that you would like me to respond to, I am happy to do that. 09:56:03 6 Q. Okay, I would. You just saw that two patients had 09:56:08 7 delusions, right? That's not on this one, it is on the sheet 09:56:13 8 I just had up. 09:56:15 9 A. Okay, yes. 09:56:16 10 Q. And we now see that eight had hallucinations, right? 09:56:21 11 A. That's correct. 09:56:22 12 Q. Now, Dr. Mann, are delusions and hallucinations the 09:56:26 13 hallmark symbols of psychosis? 09:56:33 14 A. That would represent some kind of psychotic 09:56:33 15 symptomatology, that's correct. 09:56:35 16 Q. And in your judgment, sir, is it fair to take the 09:56:43 17 real-life experiences of eight people that were having 09:56:46 18 hallucinations and round them down to zero percent in a 09:56:50 19 statistical analysis? 09:56:53 20 A. I don't understand why you think this table is doing that. 09:56:55 21 This table presents you -- and that's how you're able to make 09:57:00 22 your point -- with both the absolute number of cases that 09:57:05 23 have hallucinations, delusions, 1 case of hostility. It also 09:57:11 24 tells you the total number of subjects, patients that were 09:57:14 25 involved and that's almost 3,000. 1649 09:57:21 1 You have 8 people out of 3,000 for hostility, you 09:57:26 2 have 1 person out of 3,000, and you can calculate a 09:57:27 3 percentage which is easier for people to understand when you 09:57:31 4 have different numbers of people getting paroxetine, 09:57:34 5 different numbers of people getting placebo and different 09:57:38 6 numbers of people getting tricyclics. 09:57:42 7 It is hard to -- for a person who is going to try to 09:57:42 8 calculate a percentage across the three treatment groups, so 09:57:45 9 you need the percentage there to allow the comparison, 09:57:49 10 otherwise people have to pull out a calculator in order to 09:57:52 11 figure out what is going on. At the same time by having in 09:57:56 12 the absolute number of cases, no one is trying to hide the 09:57:58 13 exact number of cases that had all of these reports. 09:58:02 14 Now, in math we all -- there's a general principle if 09:58:09 15 you're reporting percentages and it is .1 percent and you're 09:58:13 16 rounding it up or down to the nearest percentage -- if it is 09:58:17 17 .1, that's below .5, that's going to go down to zero. If it 09:58:21 18 was .5 or .6, you would be rounding it up to 1 percent. 09:58:26 19 There's nothing mysterious or magical. This table provides 09:58:31 20 all of the data. 09:58:33 21 Q. Would you say that's sort of like what our president 09:58:37 22 described as fuzzy math? 09:58:45 23 A. This has nothing to do with fuzzy math. This tells you 09:58:49 24 the exact number of people, 8 with hallucinations, 1 with 09:58:57 25 hostility out of 3,000 patients. You have both the absolute 1650 09:59:01 1 number and the percentage. There's nothing being hidden 09:59:04 2 here. 09:59:04 3 Q. Let's look at akathisia. Here we have a 49-year-old 09:59:08 4 female who had excitement, irritability and akathisia on 09:59:13 5 day 9 on 30 milligrams, definitely related to paroxetine, 09:59:20 6 right? 09:59:22 7 A. That's what it indicates. 09:59:24 8 Q. Dr. Mann, does it offend you, having been summoned as an 09:59:29 9 expert witness for SmithKline Beecham to sit there and see 09:59:32 10 these tables where they have said yes, suicide attempt, 09:59:36 11 definitely related to our drug; yes, akathisia, definitely 09:59:42 12 related to our drug? Does that offend you? 09:59:45 13 MR. PREUSS: Objection, argumentative, Your Honor. 09:59:47 14 THE COURT: Sustained. 10:00:07 15 Q. (BY MR. VICKERY) In addition to the hallucinations and 10:00:08 16 delusions there were also three people who had psychosis and 10:00:11 17 one who had a psychotic depression, right? 10:00:25 18 A. Yes, I see that. 10:00:26 19 Q. And both of those you see also were rounded down to zero 10:00:30 20 percent, true? 10:00:32 21 A. Same response as before, they tell you exactly how many 10:00:35 22 cases had those two conditions. 10:00:41 23 Incidentally, if you look at the paroxetine data in 10:00:48 24 the ACNP task force report, you will see that we did not 10:00:53 25 address the question of emergent suicidality and some of the 1651 10:00:59 1 issues, hallucinations, delusions and all of those things 10:01:03 2 that you brought up here. It was confined to the suicides 10:01:06 3 and the suicide attempts. 10:01:08 4 We also did report that there were suicide attempts, 10:01:11 5 we just didn't attempt to attribute the cause of those 10:01:14 6 suicide attempts. We showed that the suicide attempt rates, 10:01:18 7 in fact, with the typographical correction, you see it is .04 10:01:25 8 on the paroxetine group, that's a tenth -- that's exactly the 10:01:31 9 same as the other treatment group. That's half of what you 10:01:37 10 see in the placebo group. 10:01:39 11 There's no effort here to say it was due to the 10:01:43 12 paroxetine, it wasn't due to the paroxetine. This table 10:01:46 13 explains everything: When you compare the paroxetine to the 10:01:53 14 TCA or the placebo, you don't see more suicide attempts on 10:01:57 15 the paroxetine and you don't see more suicide. 10:02:00 16 Q. Dr. Mann, if in 1992 you had seen the tables that I just 10:02:05 17 showed you this morning where SmithKline Beecham submitted a 10:02:09 18 document to the FDA that said suicide attempt, definitely 10:02:13 19 related; suicide attempt, definitely related; suicide 10:02:18 20 attempt, definitely related -- if you had seen that in 1992, 10:02:23 21 would you have written this paragraph differently? 10:02:27 22 A. If I had seen those data in 1992, I would have looked at 10:02:32 23 the rest of the report and the rest of the tables, because 10:02:35 24 clearly, as we've seen in the last day or so going through 10:02:44 25 things, taking one little thing here and one little thing 1652 10:02:44 1 there, you don't always get the whole picture. 10:02:47 2 So, you know, I'm interested in knowing what keeps 10:02:50 3 patients safe, and I treat patients. I don't sell pills. I 10:02:55 4 would go and have a look at the rest of the data. 10:02:58 5 Q. Do doctors that treat patients deserve both from the 10:03:03 6 standpoint of just medical practice and basic human morality 10:03:09 7 to have whatever relevant information the drug company has 10:03:12 8 about side effects for the patients? 10:03:19 9 A. Certainly that's the purpose of the information, labeling 10:03:24 10 information, package insert. 10:03:28 11 Q. Now, let's talk about suicide, if we may. You are a 10:03:57 12 suicidologist, correct? 10:04:00 13 A. Yes. 10:04:00 14 Q. And I have previously in taking your deposition 10:04:03 15 acknowledged that you're one of the most if not the premier 10:04:08 16 suicidologist in the world, and that's true, isn't it? 10:04:12 17 A. You may have said that. Physicians are not engaged in 10:04:27 18 beauty contests. 10:04:27 19 Q. But other people do say that about you, don't they? 10:04:28 20 A. Is that a question? 10:04:29 21 Q. Yes, sir. 10:04:30 22 A. If you say so. 10:04:32 23 Q. Okay. You were originally asked to be one of the three 10:04:35 24 authors on the comprehensive textbook of suicidality, aren't 10:04:40 25 you? 1653 10:04:40 1 A. Yes, I was. 10:04:41 2 Q. But your time commitments would not permit you to do it, 10:04:44 3 right? 10:04:45 4 A. That's correct. 10:04:45 5 Q. And so Dr. Silverman filled in instead of you? 10:04:52 6 A. He did. 10:04:53 7 Q. But you did write a jacket endorsement for this book, 10:04:56 8 didn't you? 10:04:56 9 A. I did. 10:04:57 10 Q. Let me hand it to you and just ask you to read it. 10:05:07 11 A. "Maris, Berman and Silverman" -- the three editors of this 10:05:12 12 book or writers -- "are to be congratulated on this 10:05:16 13 important new initiative. Although there have been many 14 books published in the field of suicidology, a comprehensive 10:05:19 15 textbook has been lacking. All readers who want to have 10:05:22 16 wealth of knowledge about suicide and suicidal behavior will 10:05:25 17 greatly value having this book on their shelves. Its 10:05:29 18 richness, breadth and internal consistency make it an 10:05:34 19 excellent resource for clinicians and academicians." 10:05:38 20 Q. You wouldn't have written it if you didn't mean it, would 10:05:40 21 you? 10:05:41 22 A. That's correct. 10:05:42 23 Q. Now, I want to go back to the diagram you did yesterday -- 10:05:58 24 THE COURT: If you would refer to the exhibit number. 10:06:01 25 MR. VICKERY: Thank you, Your Honor. SB-LL. 1654 10:06:04 1 Q. (BY MR. VICKERY) And I would ask you to help me complete 10:06:06 2 it, if you would. Would you mind stepping down and labeling 10:06:12 3 this little area right here? That's the prefrontal cortex, 10:06:16 4 isn't it? 10:06:19 5 A. Not exactly. The prefrontal cortex is this part of the 10:06:27 6 brain here, approximately. It is the front third of the 10:06:30 7 brain. 10:06:30 8 Q. And what would you call this little area that you've drawn 10:06:33 9 in with the hash marks that represents that portion of the 10:06:38 10 brain that affects inhibition control and suicide and 10:06:42 11 violence? What is it called? 10:06:45 12 A. That's generally called the orbital prefrontal cortex, 10:06:52 13 above the eyes, or sometimes the ventral prefrontal cortex 10:06:57 14 because ventral is this part of the brain down here, bottom 10:07:02 15 part. 10:07:03 16 Q. Is it part of the prefrontal cortex? 10:07:05 17 A. It is. 10:07:06 18 Q. Would you mind labeling it as such on your drawing -- you 10:07:11 19 do have a Magic Marker. Fine, thank you. 10:07:14 20 A. So this whole big area here is called the prefrontal 10:07:21 21 cortex and this bit here is called the ventral, I'm putting 10:07:40 22 PFC for short. 10:07:44 23 Q. Now, Dr. Mann, you explained yesterday how it has been 10:07:47 24 your goal to help really prevent all suicide by targeting 10:07:54 25 ways to affect this area of the brain, correct? 1655 10:07:59 1 A. That's not exactly what I said. 10:08:02 2 Q. Well, I don't want to put words in your mouth. That's 10:08:05 3 sort of how I understood it. 10:08:06 4 What has been your goal with respect to identifying 10:08:09 5 this area of the brain as that portion of the brain that 10:08:12 6 affects violence and suicide and doing something about it? 10:08:16 7 Just put it in your own words. 10:08:18 8 A. Well, as I said yesterday, we believe that this part of 10:08:22 9 the brain here is an important factor that determines whether 10:08:26 10 or not people act on powerful feelings and that the amount of 10:08:31 11 serotonin coming into this area of the brain plays a role in 10:08:36 12 how well this functions, and that people who are more 10:08:40 13 predisposed to act on powerful feelings such as suicidal or 10:08:44 14 homicidal feelings probably have less serotonin coming into 10:08:48 15 this area of the brain. 10:08:50 16 And I thought this might be useful one day for 10:08:53 17 clinical purposes because if we could develop a way of 10:08:58 18 imaging the brain, looking at the biochemistry of the brain, 10:09:01 19 we might be able to see, as we can already see in the brain 10:09:05 20 of people who have killed themselves, a biochemical 10:09:09 21 abnormality here while people are still alive, see -- they 10:09:13 22 order a brain scan and that might help physicians know this 10:09:16 23 patient is at risk for suicide if they've got a depression 10:09:19 24 and this patient is at lower risk for suicide if they've got 10:09:25 25 depression and the high-risk patients will get more intensive 1656 10:09:26 1 monitoring and treatment. 10:09:28 2 Q. We're not quite there yet in terms of radiology and being 10:09:31 3 able to do that, are we? 10:09:33 4 A. That's correct. 10:09:52 5 Q. Let me flip back to another chart. This is SB-II and it 10:10:28 6 was a drawing by Dr. Wheadon, I believe, to help us 10:10:28 7 understand the way that serotonin reuptake inhibitors work. 10:10:28 8 And my question to you is is this area right here 10:10:28 9 between the neurons called the synaptic cleft? 10:10:28 10 A. Yes, it is. 10:10:28 11 Q. And are we able today to measure the amount of serotonin 10:10:28 12 represented by these little red dots in the synaptic cleft of 10:10:35 13 a living human being? 10:10:36 14 A. Not directly. 10:10:38 15 Q. Okay. Now you see on this diagram that we have -- see 10:10:42 16 right here where I'm pointing, that's the reuptake pump, he 10:10:48 17 explained, and then there's several different types of 5HT or 10:10:56 18 serotonin receptors? 10:10:58 19 A. Yes. 10:10:59 20 Q. 5HT, we've labeled 1, 2 and 3. There are actually how 10:11:02 21 many different kinds now? 10:11:03 22 A. Over a dozen. 10:11:06 23 Q. A dozen? Is it your belief, sir, that the effect of SSRIs 10:11:11 24 on the 5H1 receptor in the ventral portion of the prefrontal 10:11:20 25 cortex prevents suicide? 1657 10:11:25 1 A. I don't think anybody knows that for sure. 10:11:30 2 Q. Is it your belief that that is a viable working 10:11:33 3 hypothesis? 10:12:34 4 A. It is a hypothesis. It is not the only hypothesis. If 10:12:34 5 you've got over a dozen receptors, you could start by 10:12:34 6 assuming you have got a dozen targets that you've got to 10:12:34 7 think about, but the 5HT1 receptor is one of them. 10:12:34 8 Q. Back when you wrote the Mann and Kapur you were trying to 10:12:34 9 explain biologically if there were a small group of patients 10:12:34 10 that were at risk, just how that risk occurred, weren't you? 10:12:34 11 A. That's a standard scientific approach. If you're 10:12:34 12 analyzing an alleged risk in a discussion of the evidence of 10:12:34 13 the strength of how likely that is to be an observable fact, 10:12:34 14 part of the discussion is to think about is there a viable 10:12:34 15 mechanism that might produce that risk, yes. 10:12:34 16 Q. And did you do it? 10:12:34 17 A. We did have a discussion like that. 10:12:34 18 Q. And at that time you thought about -- you postulated that 10:12:39 19 it was some kind of effect the SSRI drugs would have on the 10:12:42 20 5H1A receptor, true? 10:12:45 21 A. Yes, but not the receptor that you're looking at over 10:12:48 22 here. 10:12:50 23 Q. A 5H1 receptor in a different part of the brain? 10:12:54 24 A. That's correct. 10:12:55 25 Q. Where, basal ganglia? 1658 10:12:59 1 A. Basal ganglia? No. 10:13:06 2 Q. I got you, didn't I? 10:13:10 3 A. No, it is funny. There are no 5HT1A receptors in the 10:13:17 4 basal ganglia. Never mind. 10:13:21 5 It is in the brain stem. This is a serious topic. 10:13:23 6 Q. It is very serious. 10:13:24 7 A. That's where all the cells are located, and on the cells 10:13:29 8 and they send their fibers all the way -- all over the brain, 10:13:36 9 but it is only this section that we think is relevant, 10:13:41 10 supplying this section that matters for suicide. 10:13:43 11 Mr. Vickery, I believe, is referring to 5HT1A 10:13:48 12 receptors that are located here on the cells themselves. 10:13:52 13 Q. What you told me in your deposition in this case a few 10:13:54 14 weeks ago is that research in the intervening years has 10:13:58 15 convinced what you then thought was the biological mechanism 10:14:01 16 that could trigger violence and suicide really isn't -- it is 10:14:05 17 really not the 5H1A receptor, right? 10:14:13 18 A. That somewhat significantly misstates what I said. 10:14:17 19 Q. I don't want to do that. Please just tell me what you 10:14:21 20 said. Did you or did you not tell me that you've changed 10:14:24 21 your mind about the possibility of the 5HT1A receptor being 10:14:31 22 the potential culprit in this situation? 10:14:34 23 A. Yes, I'm happy to explain that a little more carefully. 10:14:40 24 Perhaps if I use a clean sheet of paper -- 10:14:45 25 Q. I don't mind the explanation, but if you've concluded that 1659 10:14:47 1 5HT1A is not the problem, I'm with you on that. I'm not 10:14:53 2 going to quarrel with you about it, so unless you think it is 10:14:56 3 helpful to us for you to explain why your 1991 theory is no 10:15:00 4 longer a viable one, I'd just as soon move onto something 10:15:05 5 else. 10:15:05 6 A. Okay. I will be extremely brief in that case. 10:15:08 7 Q. Okay. 10:15:12 8 A. First of all, we didn't find scientific evidence, credible 10:15:15 9 scientific evidence of a clinical association between suicide 10:15:19 10 and these SSRIs. And as I said yesterday at the very 10:15:23 11 beginning, we were surprised that one would propose such an 10:15:29 12 association because it went exactly in the opposite direction 10:15:30 13 of all of the biological data which suggested that SSRIs 10:15:37 14 should be helpful for suicidal risk, not harmful. 10:15:40 15 So in trying to think about this, the thought was, 10:15:43 16 well, what happens is maybe there is a mechanism. Maybe the 10:15:49 17 mechanism is that what happens in the brain is this, the cell 10:15:52 18 over here releases serotonin that goes into here and provides 10:15:56 19 this restraint system. 10:15:58 20 But, you give an SSRI and you produce a tremendous 10:16:02 21 surge of serotonin, but some of it is also coming back here, 10:16:05 22 like this. So here's the cell, just blowing this up with the 10:16:10 23 fiber coming like this and sending serotonin, releasing 10:16:14 24 serotonin down the -- into here, but it also has a little 10:16:18 25 fiber that comes back on itself like this, and that little 1660 10:16:22 1 fiber also releases serotonin. 10:16:24 2 And that's its feedback loop, so it is an electrical 10:16:28 3 signal. The cell fires. What stops it firing? This little 10:16:33 4 loop here, serotonin -- doesn't matter what it is doing over 10:16:36 5 here -- feeds back on itself and shuts off the firing, and 10:16:39 6 that's how the system stops firing continuously. Otherwise 10:16:43 7 you get overshoot. 10:16:44 8 It is just a feedback mechanism, very simple. The 10:16:49 9 receptor that mediates this or at least one of them is the 10:16:53 10 5HT1A receptor that you heard counsel referring to. It 10:16:57 11 mediates this feedback. We thought maybe what happens, you 10:17:02 12 get a big surge of serotonin, you get this big feedback and 10:17:06 13 you shut off the system and it becomes low in function, and 10:17:11 14 because it is low in function the person becomes vulnerable. 10:17:15 15 But now we have more sophisticated devices to measure 10:17:19 16 exactly what is going on, and, you know, what we see with 10:17:24 17 these medications is that, yes, you get a release of 10:17:28 18 serotonin, which you can't measure in the synaptic cleft, it 10:17:34 19 is too tiny, but you can measure the spillover. 10:17:38 20 What happens when they take a drug, an SSRI, the 10:17:40 21 increase in the amount of serotonin that's been -- that's in 10:17:45 22 the intrasynaptic cleft goes up progressively over a period 10:17:51 23 of weeks. It never goes down below normal. And at the time 10:17:57 24 I wrote the article we didn't know that. We thought maybe 10:18:00 25 that was a possibility. 1661 10:18:01 1 It doesn't go below normal. It goes up a little at 10:18:06 2 the beginning and progressively more and more as time goes 10:18:09 3 by, which is why the medications have a better and better 10:18:12 4 therapeutic effect as time goes by. 10:18:15 5 That's the current view of the situation. So if you 10:18:18 6 want to add anything to what we knew then, it appears not 10:18:22 7 only do we not see a clinical association with suicide or 10:18:25 8 suicide attempts, but even the mechanism that we thought 10:18:29 9 might explain such an association, if there were one and 10:18:32 10 there isn't, appears to be unsupported by new scientific 10:18:35 11 evidence. 10:18:37 12 Q. Before you take your seat back, flip the chart back for 10:18:40 13 me, if you would. 10:18:42 14 We've been talking about 5HT1A, and I want to get 10:18:46 15 back to your brain diagram there. 10:18:49 16 A. This one or the one we had before? 10:18:51 17 Q. Yes, sir. Are there any 5HT2 receptors in the ventral 10:18:58 18 portion of the prefrontal cortex? 10:19:00 19 A. Yes, there are. There are 5HT -- I think you're thinking 10:19:04 20 of the 5HT2A receptor. 10:19:07 21 Q. Would you just label that on that drawing, please, that 10:19:10 22 there are indeed 5HT2A receptors in there? 10:19:15 23 THE COURT: Would the record mention the exhibit 10:19:16 24 number? 10:19:17 25 MR. VICKERY: Yes. Once again the exhibit number is 1662 10:19:20 1 SB-LL. It has still not been admitted, Your Honor. 10:19:55 2 Q. (BY MR. VICKERY) If you would take your seat, I'm going 10:19:58 3 to ask you to read two paragraphs from the year 2000 10:20:01 4 textbook. Do you see here we're looking in the chapter on 10:20:21 5 the biology of suicide? 10:20:23 6 A. Yes, I do. 10:20:25 7 Q. And do you see that we're looking in the portion of that 10:20:28 8 chapter that discusses selective serotonin reuptake 10:20:32 9 inhibitors? 10:20:33 10 A. Right. 10:20:35 11 Q. I would like you to read, if you would, these three 10:20:38 12 sentences that I've highlighted on the second page of that 10:20:41 13 discussion. 10:20:44 14 THE COURT: What's the page number? 10:20:45 15 THE WITNESS: It is page 394, Your Honor. 10:20:50 16 A. "SSRIs have well-established efficacy for major 10:20:54 17 depression, obsessive-compulsive disorder, panic disorder and 10:21:00 18 bulimia" -- that means people who binge eat. "These 10:21:06 19 indications relate directly to the fact that SSRIs cause 10:21:10 20 desensitization of 5HT1A receptors leading to more 10:21:22 21 serotonergic transmission in the prefrontal cortex, basal 10:21:22 22 ganglia, limbic cortex/hippocampus and hypothalamus. The 10:21:29 23 stimulation of 5HT2 receptors by the SSRIs leads to possible 10:21:34 24 adverse effects of agitation, akathisia, meaning 10:21:42 25 restlessness, pacing, fidgetiness, anxiety, panic attacks, 1663 10:21:48 1 insomnia/myoclonic jerks and sexual dysfunction." 10:21:53 2 Q. In discussing the biology of suicide and SSRIs in the year 10:21:58 3 2000, the textbook that you endorsed said that stimulation of 10:22:03 4 the 5HT2 receptors by SSRIs leads, among other things, to 10:22:10 5 akathisia, true, sir? 10:22:15 6 A. Well, I should point out I did not write this chapter. I 10:22:18 7 did endorse the book. It doesn't mean I agree with every 10:22:22 8 single fact in this mammoth textbook. I want to make that 10:22:26 9 very, very clear. I agree with the facts I wrote in 10:22:30 10 scientific articles myself. 10:22:31 11 I can take responsibility, as you've pointed out, for 10:22:33 12 every word, every sentence, in those articles going back ten 10:22:37 13 years. But I can't vouch for agreeing with every single fact 10:22:42 14 in this textbook. On the whole I think the textbook is very 10:22:46 15 good and very helpful. I can't agree with every single word 10:22:49 16 in it. 10:22:50 17 Q. You're aware that another neuropsychopharmacologist, 10:22:54 18 specifically Dr. Healy, testified here last week that the 10:22:59 19 5HT2 receptor and the impact of the serotonergic drugs like 10:23:06 20 SSRIs on that receptor is a matter of extreme concern with 10:23:09 21 respect to violence and suicide? You know that he took that 10:23:15 22 view, don't you? 10:23:16 23 A. I don't. 10:23:17 24 Q. Okay. Let's move on to something else. 10:23:20 25 Yesterday you were giving a little history of the 1664 10:23:27 1 antidepressants, right? 10:23:30 2 A. Yes. 10:23:31 3 Q. And was that based on your own review or was it based on 10:23:34 4 Dr. Healy's book The Antidepressant Era? 10:23:39 5 A. I have to say that was my own work. 10:23:42 6 Q. You have read Dr. Healy's book, haven't you? 10:23:46 7 A. Parts of it. 10:23:47 8 Q. And your Rule 26 report in this case says that you 10:23:51 9 intended to talk about his book, among other things, or you 10:23:56 10 might in your testimony, right? 10:23:58 11 A. I might. 10:23:59 12 Q. Now, he chronicles the experience of zimelidine causing 10:24:05 13 Guillain-Barre Syndrome in his book, doesn't he? 10:24:10 14 A. Perhaps. 10:24:30 15 Q. In talking about the history, you talked about the MAOIs 10:24:30 16 and how they really worked, correct? 10:24:30 17 A. I did describe them briefly, that's correct. 10:24:30 18 Q. And they really worked on hospital depressions, didn't 10:24:30 19 they? 10:24:31 20 A. I don't agree with that. 10:24:32 21 Q. No? Well, the jury will remember it more. My notes say 10:24:37 22 you described the MAOIs as working on hospitalized 10:24:40 23 depression. Do you now say they don't? 10:24:43 24 A. That's simply not what I said. What I said was that the 10:24:51 25 discovery and drugs of the MAOIs was a very important 1665 10:24:56 1 breakthrough, even though they had these difficulties with 10:25:00 2 the diet and so on and so forth because we didn't have any 10:25:03 3 working antidepressants that were really any good before 10:25:06 4 that. 10:25:07 5 And I gave an illustration of patients who had been 10:25:09 6 hospitalized with depression who then took MAOIs and were 10:25:13 7 able to go home. 10:25:15 8 Q. Okay. Now, it is true, is it not, Dr. Mann, that the 15 10:25:24 9 percent mortality figure given from the Swedish study about 10:25:29 10 people that kill themselves on depression is for 10:25:33 11 hospital-based depression? That's true, isn't it, sir? 10:25:38 12 A. Which Swedish-based study are you referring to? 10:25:42 13 Q. Gusea. 10:25:45 14 A. I assume that counsel is referring to Sam Gusea who passed 10:25:52 15 away not so long ago, but he was from the Midwest and his 10:25:57 16 work with Robbins was done in the Midwest, not in Sweden. 10:26:02 17 Q. I may have misspoke. The Lundby study, is that the one 10:26:06 18 that has the 15 percent figure? 10:26:08 19 A. There were several. Lundby was Scandinavian. There are 10:26:13 20 several studies that have been carried out and estimated that 10:26:17 21 the lifetime mortality due to people suffering from 10:26:21 22 depressions was about 15 percent. 10:26:23 23 Q. And those studies are focusing on people that are -- in 10:26:26 24 hospitalized depressed patients rather than 10:26:30 25 walking-around-in-society kind of people; isn't that true, 1666 10:26:32 1 Dr. Mann? 10:26:36 2 A. Many of the patients in those studies were hospitalized, 10:26:39 3 not necessarily all of them, and I assume that what your 10:26:42 4 point is, you're really heading towards the question of the 10:26:48 5 reanalysis of those data by Bostwick and Pankrantz. 10:26:53 6 Q. I very well could be. The incidence, the risk of suicide 10:27:03 7 for people that have mild to moderate major depression, is 10:27:03 8 much lower than 15 percent, isn't it, Dr. Mann? 10:27:07 9 A. It may be lower than 15 percent, that's correct. 15 10:27:10 10 percent is an average that represents the mortality, i.e. 10:27:19 11 suicide, in people with a variety of severities of illness. 10:27:24 12 There are going to be milder depressions that have a lower 10:27:26 13 mortality due to suicide. 10:27:29 14 Q. Now, neither Paxil nor any of the other SSRIs have ever 10:27:37 15 been shown to work in hospital-based depression; isn't that 10:27:41 16 true, sir? 10:27:43 17 A. That's not correct. 10:27:45 18 Q. Well, let's look at the Paxil label. 10:27:47 19 MR. VICKERY: This is, for the record, Joint 10:27:50 20 Exhibit 200-B. 10:27:55 21 Q. (BY MR. VICKERY) And do you see here on the label where 10:27:57 22 it says, "Indications and usage: The antidepressant action 10:28:01 23 of Paxil in hospitalized depressed patients has not been 10:28:06 24 adequately studied"? 10:28:08 25 Is this label wrong? 1667 10:28:14 1 A. Where is this coming from? Are you saying this is the 10:28:16 2 package insert? 10:28:18 3 Q. That's exactly what I'm saying, the 1998 package insert. 10:28:24 4 Is it wrong? 10:28:25 5 A. You asked the question about SSRIs in general. 10:28:29 6 Q. Oh, okay. So this is -- is this right? Is Paxil not 10:28:33 7 adequately studied in hospital-based depression? 10:28:37 8 A. The amount of data available on the efficacy of Paxil on 10:28:44 9 inpatients is definitely much less. Most of the studies were 10:28:47 10 done in depressed outpatients. 10:28:48 11 Q. Now, you are as a psychopharmacologist very familiar with 10:28:57 12 the pharmacokinetic, pharmacodynamics, in other words, the 10:29:04 13 differences between the SSRI drugs, aren't you? 10:29:07 14 A. I have some knowledge of that. 10:29:10 15 Q. Is Paxil a more potent inhibitor of serotonin reuptake 10:29:14 16 than the other SSRIs? 10:29:16 17 A. Paxil has a very high affinity for blocking the serotonin 10:29:24 18 transporter or pump, as you described it. It is one of the 10:29:28 19 highest affinity drugs amongst the SSRIs, that's correct. 10:29:31 20 Q. So does this mean it is more potent in blocking the 10:29:34 21 reuptake? 10:29:35 22 A. The potency in blocking the reuptake in any individual 10:29:38 23 patient is going to be directly related to both the affinity 10:29:44 24 or how tightly the drug binds to the transporter and how much 10:29:50 25 you give of the drug. 1668 10:29:52 1 So, for example, some drugs -- some SSRIs you give 10:29:56 2 higher doses and other drugs you give lower doses. The whole 10:30:02 3 goal is to block the transporter as much as possible in order 10:30:05 4 to maximize the therapeutic effect. 10:30:09 5 Far more important in some ways than the differences 10:30:12 6 in affinity between one drug and another is the fact that the 10:30:15 7 blood level of any individual drug varies 20-fold between 10:30:25 8 people and it varies 20-fold between people because we break 10:30:28 9 down these drugs at very different rates so that you have to 10:30:31 10 titrate the dose and try to get a dose that works for each 10:30:34 11 individual patient. 10:30:36 12 Q. That's not what the package insert says, is it? It 10:30:39 13 doesn't say to titrate the dose; it doesn't say there's a 10:30:44 14 20-fold difference in patients; it just says the recommended 10:30:50 15 dose is 20 milligrams a day? Isn't that true? 10:30:55 16 A. The reason that one can -- 10:30:57 17 Q. Doctor, I don't mind you explaining, but just tell me; 10:31:00 18 isn't that true? 10:31:01 19 A. Well, I think it would be helpful -- the package insert is 10:31:04 20 several pages long. There is some discussion about metabolic 10:31:07 21 rate and that sort of stuff and the fact it might vary, and 10:31:10 22 they present ranges of the half-life of these drugs because 10:31:14 23 they vary. The half-life is directly related to the 10:31:17 24 metabolic rate. 10:31:18 25 They don't present a single number in the package 1669 10:31:21 1 insert for the metabolic rate. They present a range of 10:31:24 2 half-lives in the metabolic range, a range of hours, and 10:31:27 3 that's because it is shorter in some people because they 10:31:30 4 break it down faster and it is longer in other people because 10:31:33 5 they break it down slower, and the ones that break it down 10:31:36 6 slower are going to get a higher blood level with exactly the 10:31:39 7 same amount of pills. 10:31:42 8 Q. Would you expect that because of its potency, or to use 10:31:47 9 your words, its affinity for the reuptake -- 10:31:50 10 A. Transporter. 10:31:51 11 Q. -- transporter, that whatever side effects were going to 10:31:54 12 be caused by Paxil would happen quicker than the side effects 10:31:58 13 on the other SSRIs? 10:32:01 14 A. No, not necessarily at all. It is not a question of the 10:32:07 15 affinity, it is a question of how many transporters you 10:32:12 16 block. 10:32:12 17 Q. Okay. Tell me, if you will, which of these drugs -- 10:32:15 18 Paxil, Prozac or Zoloft -- has the greater impact on the 10:32:20 19 5HT2A receptor? 10:32:26 20 A. None of those drugs directly affect the 5HT2A receptor. 10:32:37 21 Q. They have indirect effects, right? 10:32:37 22 A. They all have indirect effects. 10:32:37 23 Q. And can you tell us which of them has the greater indirect 10:32:39 24 effect? 10:32:40 25 A. That's going to be entirely a function of the dose and the 1670 10:32:44 1 blood level and how many of the transporters you block in the 10:32:48 2 person. 10:32:49 3 Q. Okay. 10:32:50 4 THE COURT: Mr. Vickery, we will take our morning 10:32:52 5 recess. 10:32:54 6 MR. VICKERY: Very good. 10:32:55 7 THE COURT: Ladies and gentlemen, we will stand in 10:32:56 8 recess for 15 minutes. 10:33:00 9 (Recess taken 10:30 a.m. until 10:50 a.m.) 10:59:02 10 THE COURT: Dr. Mann, you understand you're still 10:59:05 11 under oath? 10:59:06 12 THE WITNESS: Yes, Your Honor. 10:59:15 13 MR. VICKERY: May I proceed, Your Honor? 10:59:17 14 THE COURT: Yes, you may, Mr. Vickery. 10:59:19 15 Q. (BY MR. VICKERY) Dr. Mann, of the 70 million 10:59:22 16 prescriptions a year you mentioned yesterday for the SSRIs, 10:59:26 17 would it be fair to say the big three -- Zoloft, Paxil and 10:59:32 18 Prozac -- comprise the vast majority of those? 10:59:36 19 A. I'm not an expert in the marketing figures for SSRIs, but 10:59:41 20 I believe that that is correct. 10:59:43 21 Q. I mean, one of them in this country, Luvox, cannot even be 10:59:48 22 marketed for depression, right? 10:59:52 23 A. Its indication is principally OCD, obsessive-compulsive 10:59:59 24 disorder. 11:00:00 25 Q. And it doesn't have a depression indication, though, does 1671 11:00:03 1 it? 11:00:04 2 A. That's correct, although physicians do use it for 11:00:06 3 depression as well. 11:00:07 4 Q. The fifth one, Celexa, just came on the market in the 11:00:11 5 country a couple years ago? 11:00:14 6 A. Recently, yes. 11:00:15 7 Q. Remember, we were talking about whether these drugs were 11:00:17 8 studied adequately for hospital-based depression? 11:00:20 9 A. Yes. 11:00:21 10 Q. Well, the package inserts for both Prozac and Zoloft are 11:00:25 11 in evidence. They're Joint Exhibits 229 and 230, and I'm 11:00:35 12 going to give those to you. For your convenience I have 11:00:38 13 highlighted the portions that deal with hospital-based 11:00:42 14 depression, so if you would flip to the highlighted portion 11:00:45 15 and tell us whether Prozac or Zoloft have been adequately 11:00:51 16 studied in hospital-based depression. 11:01:10 17 A. Given that, of course, this is a product information and 11:01:17 18 not necessarily a systematic review of literature the way 11:01:23 19 others might do it, it says here in the Prozac product 11:01:28 20 information on page 895, "The antidepressant action of Prozac 11:01:33 21 in hospitalized depressed patients has not been adequately 11:01:38 22 studied." 11:01:39 23 Q. And would you have a look at the Zoloft label and see if 11:01:43 24 it doesn't say the same thing? 11:02:04 25 A. "The antidepressant action of Zoloft in hospitalized 1672 11:02:09 1 depressed patients has not been adequately studied." Same 11:02:12 2 wording. 11:02:13 3 Q. All right. Now, let me take those back, if I may. 11:02:22 4 MR. VICKERY: Your Honor, SB-LL, this drawing, was 11:02:27 5 offered yesterday and I asked the Court to withhold ruling on 11:02:29 6 it until I had a chance to cross-examine the witness on it, 11:02:33 7 and I will join in the offer of that exhibit at this point. 11:02:36 8 THE COURT: Very well. Defendant's Exhibit LL may be 11:02:39 9 received in evidence. 11:02:42 10 (Defendant Exhibit SB-LL received in evidence.) 11:02:44 11 MR. PREUSS: Your Honor, I would like to offer, while 11:02:46 12 we're on that, MM, and then I marked the last drawing NN, at 11:02:52 13 this time. 11:02:53 14 MR. VICKERY: Let's see which ones they are. 11:03:01 15 MR. PREUSS: That would be MM, there's two pages, and 11:03:08 16 then I marked that and asked that that could be NN. 11:03:11 17 THE COURT: Do we have an exhibit sticker on both 11:03:13 18 pages? 11:03:14 19 MR. VICKERY: We do not. 11:03:16 20 MR. PREUSS: I will get one on the second page, Your 11:03:18 21 Honor. 11:03:18 22 THE COURT: All right. 11:03:19 23 MR. VICKERY: I have no objection. 11:03:20 24 THE COURT: Defendant's Exhibit MM may be received in 11:03:24 25 evidence. And did you also mention NN? 1673 11:03:27 1 MR. PREUSS: Yes, Your Honor, that would be the last 11:03:28 2 drawing that Dr. Mann drew right before the break, if you 11:03:32 3 recall that. 11:03:33 4 THE COURT: During cross-examination? 11:03:34 5 MR. PREUSS: Right. 11:03:34 6 THE COURT: Any objection? 11:03:35 7 MR. VICKERY: No, sir. 11:03:35 8 THE COURT: NN may be received in evidence. 11:03:38 9 (Defendant Exhibits SB-MM, SB-NN received in evidence.) 11:03:40 10 Q. (BY MR. VICKERY) Let's talk, if we may, about the biology 11:03:43 11 or neurobiology of violence and suicide, okay? 11:03:50 12 Are they, both violence and suicide, almost always by 11:03:55 13 definition multifactorial? 11:04:00 14 A. Yes, they are. 11:04:03 15 Q. And is one of the factors that triggers them in your 11:04:09 16 experience invariably biological? 11:04:13 17 A. That's not how we look at it. First of all, the notion 11:04:20 18 that they're multi-factorial means that in any -- in people 11:04:24 19 who commit suicide, for example, one factor is almost 11:04:29 20 invariably present, that is, they have a psychiatric 11:04:32 21 condition. And then there are usually other factors required 11:04:36 22 as well which explain why not all depressed patients kill 11:04:39 23 themselves. So there are differences between the people at 11:04:43 24 risk for suicide and the people who aren't at risk for 11:04:46 25 suicide. 1674 11:04:47 1 Where does biology fit into this? To answer your 11:04:50 2 question, the biology of the brain is an aspect of everything 11:04:55 3 we do, think and experience. You know, all of our feelings, 11:05:03 4 ideas, thoughts, speech, impulses and so on and so forth are 11:05:06 5 not taking place in some magic spot. They're taking place in 11:05:11 6 a physical organ, the brain. 11:05:14 7 So you can measure and detect the biological effects 11:05:18 8 of genetics, parenting, stress and psychiatric illnesses. 11:05:27 9 Q. Okay. I can dig it out if you like, but haven't I asked 11:05:30 10 you at least on two previous occasions under oath if one of 11:05:34 11 the factors always affecting suicide is biological and 11:05:38 12 haven't you told me that it was? 11:05:42 13 A. If you would like to refer to the specific place, I think 11:05:45 14 you will find that my response was almost exactly the same as 11:05:49 15 it is today. 11:05:50 16 Q. Okay. I will do that momentarily. 11:06:32 17 MR. VICKERY: This is page 53, Counsel, of Dr. Mann's 11:06:36 18 deposition in this case. 11:06:38 19 Q. (BY MR. VICKERY) I will read the questions I asked you. 11:06:39 20 This is just a few weeks ago, right? 11:06:45 21 A. Yes, April 12th. 11:06:47 22 Q. Of this year? 11:06:48 23 A. Yes. 11:06:49 24 Q. And I'm going to read the questions I asked you and please 11:06:52 25 just read the answer that you gave under oath at that date 1675 11:06:56 1 without elaboration. 11:06:58 2 Starting on line 5, "A couple of quick things: Is 11:07:02 3 suicide by nature multi-factorial? 11:07:05 4 A. "The factors that trigger are multifactorial, yes. 11:07:12 5 Q. "Is one of them almost invariably biological? 11:07:15 6 A. "Well, the brain is biological so everything goes on in 11:07:19 7 the brain, biology always plays a role. 11:07:23 8 Q. "And is serotonin related to aggression and suicide? 11:07:27 9 A. We believe so, yes." 11:07:29 10 Q. Okay. Now, would you find, then, since we're -- we've got 11:07:33 11 the practice here of writing down everything and putting it 11:07:37 12 into evidence, would you just mind writing for me suicide is 11:07:41 13 multi-factorial and biological? 11:08:15 14 A. I don't understand why I should write -- this is your 11:08:18 15 statement, not mine. 11:08:19 16 Q. You said suicide is multi-factorial, didn't you? 11:08:24 17 A. If you would like me to write what I said, I would be 11:08:25 18 happy to, but I'm not sure what -- 11:08:25 19 Q. We just read what you said. 11:08:27 20 THE COURT: Let's not have the conversation between 11:08:29 21 the witness and counsel. Let's have the witness -- if he's 11:08:33 22 going to make an exhibit, let's have him make an exhibit 11:08:36 23 based upon what he said. 11:08:40 24 And tell us what you said, Doctor. 11:08:43 25 THE WITNESS: Thank you, Your Honor. 1676 11:09:02 1 A. All functions in the brain have a biological component. 11:09:16 2 Q. (BY MR. VICKERY) Fine. Would you mind initialing that 11:09:18 3 for us so we remember you did it? 11:09:20 4 A. Okay. 11:09:36 5 MR. VICKERY: We will label that as Plaintiff's 11:09:39 6 Exhibit 62 and I'll offer it at this time, Your Honor. 11:09:41 7 MR. PREUSS: No objection. 11:09:43 8 THE COURT: Plaintiff's Exhibit 62 is received in 11:09:44 9 evidence. 11:09:46 10 (Plaintiff Exhibit 62 received in evidence.) 11:09:47 11 Q. (BY MR. VICKERY) Now, by multi-factorial do you mean that 11:09:51 12 there are always a number of different causes that operate 11:09:55 13 concurrently to result in a suicide? 11:10:03 14 A. Our hypothesis is that suicides are usually explained by 11:10:09 15 more than one factor. 11:10:11 16 Q. So even in someone that's depressed, you expect there to 11:10:17 17 be something else in addition to the depression that is 11:10:21 18 triggering the suicide, right? 11:10:23 19 A. That's correct. 11:10:23 20 Q. Have you had any occasion since you've been here in 11:10:27 21 Cheyenne to share those thoughts with Dr. Merrell who will be 11:10:30 22 testifying this afternoon? 11:10:33 23 A. Dr. Merrell? 11:10:34 24 Q. Yes, this tall, handsome gentleman raising his hand right 11:10:39 25 there. 1677 11:10:42 1 A. It would not be correct to say I've had a conversation 11:10:45 2 with him about these kinds of matters. 11:10:47 3 Q. Okay. Now, in your report you said that Don Schell's 11:11:01 4 actions were undoubtedly caused by depression plus something 11:11:08 5 else, right? 11:11:11 6 A. I prefer to look at the exact language, since we're all so 11:11:17 7 particular about that. 11:11:36 8 Q. Do you have your report there? 11:11:37 9 A. Yes, I do. Where are you -- where would you like to 11:11:41 10 begin? 11:11:42 11 Q. I tell you what we'll do, we will put it right up here so 11:11:46 12 we can all see it. 11:11:52 13 In paragraph 29 of your report did you say, "There 11:11:56 14 are usually several factors involved in any suicide and also 11:12:01 15 in any suicide/homicide"? 11:12:08 16 A. Yes, "There are usually several factors involved in any 11:12:12 17 suicide and also in any suicide/homicide," correct. 11:12:20 18 Q. While we're talking about suicide/homicide, you have been 11:12:23 19 active in all the major professional organizations in this 11:12:27 20 country dealing with suicide for years, haven't you? 11:12:30 21 A. I've been involved with at least a couple of them, yes. 11:12:32 22 Q. And you feel like you know all of the major players, if 11:12:38 23 you will, in the field of suicidology, don't you? 11:12:43 24 A. I would say I know most of the people who are leading 11:12:46 25 investigators and experts in the field, that's true. 1678 11:12:51 1 Q. Like you know Dr. Maris and Dr. Berman and Dr. Silverman, 11:12:59 2 don't you? 11:13:04 3 A. Yes, I do. 11:13:04 4 Q. And you know Dr. Shneidman who wrote an endorsement and 11:13:04 5 Dr. Maltsberger who is our witness who also wrote an 11:13:10 6 endorsement? You know those gentlemen, don't you? 7 A. I do know them, yes. 11:13:16 8 Q. Did you ever meet Ken Tardiff? 11:13:18 9 A. Yes. 11:13:19 10 Q. Where did you meet him? 11:13:22 11 A. I was at Cornell for ten years, and we overlapped. 11:13:26 12 Q. You've never seen him at any of these functions, any of 11:13:27 13 these meetings of the American Association of Suicidology or 11:13:31 14 anything, have you? 11:13:32 15 A. Not to my knowledge, but I've only been to two meetings of 11:13:35 16 the American Association of Suicidology, so if he was a 11:13:37 17 regular attender himself he might have seen me. 11:13:42 18 Q. In paragraph 29 of your report you wrote that, "What other 11:14:01 19 factors may have played a role remain unknown," true, sir? 11:14:08 20 A. What other factors in addition to the ones I mentioned 11:14:13 21 earlier in that paragraph. 11:14:16 22 Q. Right. And then, again, in paragraph 31 you wrote, 11:14:20 23 "Therefore, we do not know and will likely never know exactly 11:14:24 24 what other factors contributed to this suicide," true? 11:14:29 25 A. That's correct. 1679 11:14:32 1 Q. You know there are some, you just don't know what they 11:14:34 2 are? 11:14:35 3 A. That's correct. 11:14:48 4 Q. We do know he was on Paxil, don't we? 11:14:51 5 A. We know a lot of things about Mr. Schell. 11:14:53 6 Q. We do know he was on Paxil, don't we? 11:14:57 7 A. That's one piece of information, yes. 11:14:58 8 Q. We do know the amount of Paxil in his blood was consistent 11:15:04 9 with someone who had taken Paxil for a couple of days, don't 11:15:08 10 we? 11:15:09 11 A. That's correct. 11:15:10 12 Q. Dr. Mann, have you ever in your experience seen a 11:15:15 13 situation like this one where a 60-year-old male with no 11:15:21 14 prior history of violence, no prior suicide attempt, anything 11:15:28 15 like that, committed an unspeakable act like this without 11:15:33 16 there being some kind of organic problem, something wrong 11:15:36 17 with their body? Have you ever seen one? 11:15:41 18 A. I'm puzzled by your question. I don't understand what you 11:15:45 19 mean by something wrong with their body. 11:15:47 20 Q. I'm talking about something organically wrong, like a 11:15:50 21 brain tumor, for example? 11:15:53 22 A. No, that's not correct. If you look at -- and I'm sure 11:15:57 23 you've discussed this with Dr. Tardiff at some length, but if 11:16:01 24 you look at the kinds of psychiatric diagnoses which are 11:16:04 25 associated with the compounded tragedy of suicide/homicide, 1680 11:16:11 1 you will see that the most -- the diagnosis that comes up 11:16:19 2 commonly, at least -- for example, there are two studies, in 11:16:23 3 one 3 out of 4 individuals had a major depression and in the 11:16:28 4 other study 4 out of 4 had a mood disorder. 11:16:33 5 So a male who is depressed is, in a sense, one of the 11:16:38 6 prototypical groups that are at risk for this terrible 11:16:42 7 consequence. 11:16:43 8 Q. Maybe my question wasn't clear. No one disputes that. 11:16:47 9 My question was that in addition to depression, have 11:16:52 10 you ever seen a person who with no history of violence or 11:16:57 11 suicidal behavior did something like this and there wasn't 11:17:01 12 some additional biological factor at work? Ever seen one? 11:17:09 13 A. Well, first of all, you have to remember that the way in 11:17:13 14 which we can study individuals who commit suicide is by doing 11:17:20 15 an analysis, biochemical analysis of brain tissue. 11:17:28 16 In most of the patients that we do these analyses in 11:17:30 17 we find evidence of these kinds of biological abnormalities. 11:17:34 18 In other words, we've got an indication biologically anyway 11:17:37 19 of this kind of predisposition that exists prior to the 11:17:42 20 development of, say, depression or whatever the illness is 11:17:46 21 that caused them to feel suicidal. 11:17:48 22 Q. I appreciate that information, but I would appreciate your 11:17:52 23 direct answer to my question. 11:17:55 24 Have you ever seen an instance where someone with no 11:17:57 25 history of violence or suicide attempt did something like 1681 11:18:00 1 this and there was not something physically wrong with them? 11:18:09 2 A. You mean specifically suicide/homicide or suicide? 11:18:13 3 Q. Either. 11:18:15 4 A. All right. Let's stick to suicide since I believe 11:18:18 5 Dr. Tardiff is the expert testifying in suicide/homicide and 11:18:22 6 my expertise is in suicides more specifically. 11:18:29 7 We don't systematically go around testing all of the 11:18:32 8 suicides to try and see whether there is this biochemical 11:18:36 9 abnormality in all of the cases of suicide that I may have 11:18:40 10 ever seen. 11:18:41 11 So I can't answer your question that way. What I can 11:18:43 12 say is in those situations where the family has given us 11:18:49 13 permission to do the analysis on the brain, the vast majority 11:18:53 14 of those cases have evidence of these kinds of biochemical 11:18:56 15 abnormalities indicating that the person had a predisposition 11:19:00 16 to suicidal behavior that was there all -- 11:19:03 17 Q. Let me cut to the chase why I asked this. Dr. Maltsberger 11:19:11 18 testified the other day he's been reading and studying about 11:19:12 19 suicide for 41 years and he's never seen any instance where 11:19:16 20 someone with no history of violence or suicidal behavior did 11:19:21 21 something like this unless there was something organic, 11:19:25 22 something biological present. 11:19:27 23 Do you have any reason to disagree with him on that 11:19:29 24 point? 11:19:30 25 A. I certainly don't have any reason to disagree with 1682 11:19:34 1 Dr. Maltsberger's experience clinically. It is obviously 11:19:38 2 vast. I'm just saying that when you look at the literature 11:19:41 3 systematically as to what was the problem in individuals who 11:19:48 4 perpetrated a suicide/homicide, you find that the commonest 11:19:52 5 thing is they tend to be men and psychiatrically the 11:19:59 6 diagnosis that stands out is that they suffer from a mood 11:20:01 7 disorder. 11:20:02 8 Now, do they have other abnormalities in addition to 11:20:05 9 that? There isn't a systematic set of reports in the 11:20:09 10 literature indicating that they have brain tumors or head 11:20:11 11 injury or, I don't know, things wrong with the rest of their 11:20:16 12 bodies. 11:20:17 13 Q. Okay. Let's follow up on that. Do the brain stems of 11:20:34 14 people who have completed suicide have low 5HIAA? 11:20:44 15 A. Is that a yes or no question? 11:20:45 16 Q. Yes, sir, it is. 11:20:49 17 A. Most studies have found that there are lower levels of 11:20:54 18 5HIAA in the brain stems of people who commit suicide. 11:21:22 19 Q. And we have been talking about 5HT. That's serotonin. 11:21:28 20 We've been talking about that for weeks now. 11:21:31 21 Will you tell the jury what 5HIAA is? 11:21:34 22 A. 5HIAA is the breakdown product of serotonin. So every 11:21:38 23 time a bit of serotonin is released, a small fraction of that 11:21:41 24 doesn't make it back safely into the cell for recycling and 11:21:45 25 reuse. Some of it is broken down. 1683 11:21:47 1 And what is it broken down to? It is broken down to 11:21:51 2 this stuff 5HIAA. So you can get a sense of how much 11:21:55 3 serotonin is being released and how active the serotonin 11:21:57 4 system is by measuring, if you like, sort of the waste 11:22:02 5 production of the breakdown product of 5HIAA. 11:22:05 6 I want to point out, because we're in a court of law 11:22:10 7 and not having a chummy talk with each other, but that 11:22:14 8 statement isn't exactly what I said. What I said was that 11:22:17 9 most studies find that in a group of people that commit 11:22:20 10 suicide that they have lower levels of 5HIAA in the brain 11:22:23 11 stem. But everybody finds this and it doesn't seem to 11:22:26 12 necessarily apply to every case. 11:22:28 13 Q. Should I put the word "most" in front of it? 11:22:31 14 A. You can write whatever you like. 11:22:34 15 Q. Well, I want to be accurate here. 11:22:36 16 Now, I'm not doing real well with yes or no questions 11:22:40 17 so I'm going to try multiple choice, okay? 11:23:21 18 Sir, would you be so kind to step to the board and 11:23:24 19 fill out the answer to the question I've wrote? 11:23:27 20 A. This is about the most misleading piece of information 11:23:30 21 you've heard this morning. I can explain why. 11:23:33 22 Q. I'm going to ask you to do that. If you will just answer 11:23:37 23 my question, we will do just fine. 11:23:40 24 A. Okay. 11:23:41 25 Q. What you have checked is the box that says, "Paxil lowers 1684 11:23:46 1 5HIAA," correct? 11:23:47 2 A. Correct. 11:23:48 3 Q. And so what -- our starting point for this discussion is 11:23:53 4 that most suicide victims have low 5HIAA, and that Paxil 11:24:00 5 lowers 5HIAA, right? 11:24:04 6 A. Correct. 11:24:04 7 Q. Now, you have already told us today that your knowledge 11:24:11 8 about the -- or your belief about the bioneurological means 11:24:21 9 whereby SSRI drugs might have caused suicide -- what you 11:24:25 10 thought back in 1991 turned out not to be true, correct? 11:24:32 11 A. That's correct. 11:24:32 12 Q. And tell the ladies and gentlemen of the jury, if you 11:24:38 13 would, Doctor, of the 12 or so receptors for 5HT, how many 11:24:45 14 have been discovered in the last five years? 11:24:50 15 A. Probably a third of them. 11:24:51 16 Q. So we're discovering things all of the time about the 11:24:54 17 serotonin system, aren't we? 11:24:56 18 A. That's correct. 11:24:57 19 Q. Okay. I know you would like to explain to us why it is 11:25:00 20 misleading to point out that suicide victims have low 5HIAA 11:25:05 21 and Paxil lowers 5HIAA, so have at it. 11:25:10 22 A. The reason is as follows: The reason -- when you find -- 11:25:18 23 when you measure serotonin function in the brain stem of 11:25:22 24 individuals who have committed suicide, you find 5HT is low 11:25:31 25 and 5HIAA is low. Both of them are low. 1685 11:25:35 1 And then when you look at different types of 11:25:37 2 receptors, the whole clinical picture that emerges -- and 11:25:42 3 we've measured lots of these receptors. We've measured lots 11:25:46 4 of these receptors than any other place -- is of a serotonin 11:25:51 5 deficiency. There's not enough activity in the system. It 11:25:55 6 is reduced in activity. 11:26:00 7 Paxil and other medications that increase serotonin 11:26:04 8 function by blocking the transporter, I repeat, increase 11:26:09 9 serotonin function. They don't decrease it as this would 11:26:13 10 suggest. I mean, if you took the real simple-minded view, 11:26:20 11 5HIAA is low in suicide, 5HIAA is lowered in people taking 11:26:25 12 these types of antidepressants like Paxil, therefore the 11:26:29 13 antidepressant is making people look biologically like 11:26:33 14 somebody who commits suicide, it is exactly the opposite. 11:26:37 15 The only reason the 5HIAA level drops in people 11:26:44 16 taking these types of antidepressants is that they are so 11:26:48 17 effective at cranking up the amount of serotonin available 11:26:53 18 and improving serotonin transmission that the brain actually 11:26:59 19 slows down the production of serotonin. It doesn't even need 11:27:03 20 as much. And the amount of 5HIAA that's produced actually 11:27:08 21 begins to go down. It is only because these drugs are so 11:27:12 22 good at increasing serotonin function that the 5HIAA begins 11:27:16 23 to drop. So it is exactly the opposite. 11:27:21 24 In the suicide victims, number one, you have low 11:27:25 25 5HIAA because you have low serotonin function. In the people 1686 11:27:28 1 who are being treated with Paxil, you have enhanced serotonin 11:27:34 2 function, better serotonin function, so good, as a matter of 11:27:37 3 fact, the brain begins to sort of try and produce less 11:27:41 4 serotonin because it doesn't need as much anymore. 11:27:43 5 Q. Okay. Thank you. 11:27:46 6 I thought you said earlier that it is not possible to 11:27:48 7 measure the amount of serotonin in the synaptic cleft. True 11:27:54 8 or not true? 11:27:55 9 A. That's correct. 11:27:56 10 Q. Now, Dr. Wheadon when he was here on Friday drew us this 11:28:07 11 little diagram. It is in evidence as SB-II. And he said 11:28:13 12 that Paxil doesn't really cause more production of serotonin, 11:28:18 13 he just -- it keeps it in this space right here longer. 11:28:22 14 Are you saying now he's wrong and that really does 11:28:25 15 affect the production and the metabolization of serotonin? 11:28:33 16 A. No. And actually yesterday I spoke about this subject as 11:28:36 17 well. I don't disagree with that at all. What I'm saying 11:28:40 18 simply is that these medications like Paxil block that little 11:28:47 19 pump or transporter over there and that leaves the serotonin 11:28:51 20 around for a lot longer. 11:28:54 21 While the serotonin is sitting in that intrasynaptic 11:28:58 22 cleft, it is sending a signal, it is firing and transmitting, 11:29:05 23 if you like. So it is so good at doing that, that even 11:29:09 24 though the patient may have started out with less serotonin 11:29:12 25 than they needed, these medications make even the reduced 1687 11:29:15 1 amount of serotonin work so well that the brain begins to 11:29:21 2 crank back on the amount of serotonin that's there, and 11:29:25 3 that's why the 5HIAA begins to drop. 11:29:29 4 And you can measure the 5HIAA, and we don't stick a 11:29:33 5 needle in people's brains. We take some spinal fluid which 11:29:38 6 has all of the 5HIAA coming from the brain and we measure the 11:29:42 7 5HIAA in that. That's what counsel is referring to. 11:29:45 8 We can see that over a period of weeks, because it 11:29:51 9 doesn't happen the first day -- over a period of weeks the 11:29:55 10 5HIAA in the patients treated with these kinds of medications 11:29:58 11 begins to gradually decline, but the serotonin function is 11:30:01 12 actually increasing. 11:30:05 13 Q. Okay. How much serotonin is in the body? 11:30:15 14 A. In what sense? 11:30:16 15 Q. I mean, how much? All of us in this courtroom, how much 11:30:20 16 serotonin do we have, on average, in our bodies? 11:30:24 17 A. Well, serotonin is in the brain, it is in the gut and it 11:30:27 18 is in the platelets which circulate in the blood and plug 11:30:31 19 holes in blood vessels. I guess is there a pound, a 11:30:35 20 kilogram, is there 20 pounds? No, it is a very tiny amount. 11:30:39 21 Q. Like then 20 grams? 11:30:41 22 A. Yes. 11:30:41 23 Q. Less than 20 milligrams? 11:30:45 24 A. Well, the whole body? I'm not sure about that. 11:30:50 25 Q. About 20 milligrams? 1688 11:30:55 1 A. The total amount in the body, 20 milligrams? I think 11:30:59 2 that's a little high, but it might be that far off. Might be 11:31:04 3 the right order of magnitude. 11:31:07 4 Q. So we're going to take a 20-milligram pill every day to 11:31:10 5 regulate the amount of a substance in the body, and there's 11:31:15 6 only 20 milligrams of that whole substance in the whole body, 11:31:18 7 right? 11:31:19 8 A. The amount of the pill has nothing to do with the amount 11:31:21 9 of serotonin. They're completely unrelated. 11:31:24 10 Q. Okay. I want to talk about warnings for a minute. What 11:31:42 11 are the role of warnings or package inserts? 11:31:43 12 A. Well, the role is to provide information about medication 11:31:46 13 that's being used in terms of some information about its 11:31:52 14 pharmacology, its metabolism, its half-life, the doses that 11:32:05 15 ought to be used, its indications, side effects and reports 11:32:14 16 of things that have happened when people have taken the 11:32:14 17 medication, whether we know it is because of the medication 11:32:16 18 or not, and a lot of other information. There's a lot of 11:32:19 19 detail in there. 11:32:21 20 Q. Is it designed to help the physician do his job? 11:32:26 21 A. Of course I'm testifying from the point of view of the 11:32:29 22 physician, not the person at FDA or the regulator or the 11:32:33 23 pharmaceutical company. I'm sure Dr. Wheadon would be much 11:32:36 24 better placed to discuss those aspects. 11:32:39 25 From the point of view of a physician prescribing 1689 11:32:42 1 medication, they're supposed to help us do a better job in 11:32:46 2 terms of deciding what dose to use in the patients and what 11:32:48 3 side effects to look out for. 11:32:50 4 Q. I want to look at a paragraph of your report. It is 11:32:52 5 paragraph 22. You're talking here about the physician's 11:33:17 6 role, right, and you say, "It is up to the physician to make 11:33:20 7 a reasonable clinical judgment as to how the management of 11:33:23 8 the patient should be modified in light of the patient's 11:33:26 9 evolving clinical picture. Such actions may include 11:33:30 10 increasing or decreasing the dose of the medication, adding 11:33:35 11 adjunctive medications or perhaps for some patients 11:33:39 12 hospitalization." 11:33:42 13 Now, I want to ask you about each of those things. 11:33:45 14 With respect to the dose, when you start a patient that has a 11:33:51 15 depression but with an anxiety component to it on Paxil do 11:33:59 16 you tell them to cut that pill in half for the first few 11:34:01 17 days? 11:34:02 18 A. The interesting thing about that question is that when you 11:34:05 19 look at the control clinical trials that have looked at the 11:34:11 20 effect of Paxil and the overwhelming prescription practice in 11:34:20 21 the U.S. and overseas -- actually, you start people off on 20 11:34:24 22 milligrams, but if you look at the control clinical trials, 11:34:29 23 in depression you find that -- and those trials used 20 11:34:35 24 milligrams as a starting dose, that whether the patient was 11:34:39 25 anxious to begin with or whether the patient became anxious 1690 11:34:42 1 or even if they're an older patient that tends to have more 11:34:47 2 anxiety with their depression, the efficacy of Paxil in those 11:34:52 3 trials was unquestionably present. 11:34:56 4 Not only that, in several clinical trials Paxil was 11:35:00 5 superior to Prozac and to fluvoxamine, which is another 11:35:10 6 antidepressant, SSRI, in terms of the antianxiety effect. 11:35:14 7 So it is not clear that the -- Paxil actually seems 11:35:18 8 to be one of the antidepressants, in fact, one of the SSRIs 11:35:25 9 that is both best tolerated in the anxious depressed patient 11:35:30 10 and also the most beneficial for the anxiety component of the 11 depression. 11:35:36 12 Q. I appreciate all of that information about the clinical 11:35:39 13 trials, but I wasn't asking about the clinical trials. I was 11:35:42 14 asking about what you do when you start a patient on Paxil 11:35:45 15 and that patient has an anxious component to their 11:35:48 16 depression. 11:35:49 17 Do you tell them to cut the pill in half for the 11:35:53 18 first few days? 11:35:54 19 A. No, I tell them to start with 20 milligrams. 11:35:57 20 Q. Are you aware of the fact that SmithKline Beecham trains 11:36:00 21 its salespeople to recommend to doctors that they do titrate 11:36:05 22 the dose or cut it in half for anxious depressed people? 11:36:09 23 A. I appreciate the question, but I think that most people 11:36:13 24 here would appreciate I'm not an expert on SmithKline 11:36:15 25 Beecham's training practices for their sales force. And 1691 11:36:19 1 Dr. Wheadon would be the logical person to have responded to 11:36:23 2 that. 11:36:23 3 Q. Actually, we've heard testimony from the salesman himself 11:36:26 4 that says that's how he was trained. The fellow that called 11:36:30 5 on the doctor that prescribed the Paxil for Dr. Schell said 11:36:34 6 that's how he was trained. 11:36:35 7 MR. PREUSS: I'll object to the mischaracterization 11:36:37 8 of the testimony of our representative. The testimony is 11:36:43 9 what it is. It mischaracterizes it. 11:36:46 10 THE COURT: Rephrase the question, if you would, 11:36:48 11 please. 11:36:48 12 MR. VICKERY: Let me pass on that. I'm sure the jury 11:36:51 13 will remember that much better than I will, Your Honor. 11:36:53 14 Q. (BY MR. VICKERY) How about adding adjunctive medications? 11:36:56 15 You're talking about benzos, aren't you? 11:37:00 16 A. Not necessarily. 11:37:02 17 Q. Let me be -- let me ask you a very specific question, and 11:37:06 18 please try to answer it very specifically. 11:37:09 19 Have you ever prescribed a benzodiazepine to be taken 11:37:14 20 conjunctively or at the same time with a SSRI drug when you 11:37:18 21 were starting the patient on that SSRI drug? 11:37:22 22 A. Almost never. 11:37:23 23 Q. Almost never? All right. 11:37:27 24 Do you prescribe some other type of sedative 11:37:32 25 medication with SSRI drugs when people start on them? 1692 11:37:36 1 A. No, that's not my practice. And that's in agreement, 11:37:40 2 actually, with the massive study that I mentioned yesterday, 11:37:43 3 the Inman study with 13,000 patients receiving Paxil where I 11:37:48 4 think it was 8 or 9 percent of those patients had received 11:37:52 5 concomitant benzodiazepines. 11:37:54 6 Q. Have you seen the German warning for Paxil -- the German 11:37:59 7 label -- it is not really a warning -- the German label for 11:38:02 8 Paxil? 11:38:07 9 A. As I said, no. 11:38:07 10 Q. Let me show it to you. 11:38:39 11 We will find it and come back to it. 11:38:42 12 How important is a history of prior violent acts in 11:38:46 13 predicting suicide or violence? 11:38:49 14 A. Prior behavior is very valuable as a predictor of future 11:38:53 15 behavior, and that's true of suicide or serious violence. 11:38:56 16 Q. So a prior suicide attempt would be a strong predictor of 11:38:59 17 suicide? 11:39:00 18 A. Yes. 11:39:00 19 Q. And a prior violent action would be a strong predictor of 11:39:06 20 future violence or suicide? 11:39:07 21 A. It would be a predictor, yes. 11:39:21 22 Q. Did you write your report yourself? 11:39:24 23 A. Every word. 11:39:25 24 Q. I just wondered why you used the word "we" in paragraph 11:39:29 25 18. Is that kind of the royal we or -- 1693 11:39:34 1 A. I sometimes use terminology like that when I feel that the 11:39:38 2 scientific information that has contributed to the point of 11:39:43 3 view was generated by, you know, other investigators. I 11:39:49 4 don't want to create the impression that it is all my own 11:39:52 5 work and ideas and so on and so forth. 11:40:01 6 Q. This is Plaintiff's Exhibit 1 and this is the label for 11:40:10 7 Paxil, and actually they call it something else, Seroxat, in 11:40:17 8 the Federal Republic of Germany. You see the paragraph where 11:40:21 9 "Paroxetine does not have a generally sedative effect. 11:40:24 10 Occasionally in patients with acute suicidal tendencies and 11:40:28 11 in patients who suffer from marked restlessness and insomnia 11:40:32 12 adjuvant sedative therapy may be necessary"? Have you ever 11:40:36 13 seen that before? 11:40:39 14 A. I'm not sure -- I mean, I don't know what document this 11:40:42 15 is. I can read the sentence like anybody else. What would 11:40:45 16 you like me to comment on? 11:40:47 17 Q. Were you aware that the parallel provision for Prozac 11:40:52 18 actually says in big capital letters, "Risk of suicide"? 11:40:58 19 A. What are you referring to? 11:40:59 20 Q. I'm talking about the German label for Prozac. 11:41:01 21 A. You know, I don't have the German labels in front of me. 11:41:04 22 I really can't comment on them. I don't know who produces 11:41:07 23 the German label. I don't know what the regulatory 11:41:11 24 requirements are for the German label. I don't know who 11:41:14 25 decides what goes in it or doesn't go in it, what the basis 1694 11:41:18 1 for those decisions are, so on and so forth. I can comment 11:41:23 2 on the U.S. a lot better. 11:41:28 3 Q. Would you agree with me that the biological response of 11:41:33 4 people in the Federal Republic of Germany to psychoactive 11:41:39 5 drugs is probably going to be about the same as the 11:41:41 6 biological response of people in this country to those drugs? 11:41:44 7 A. You would certainly think so. And in that regard, of 11:41:47 8 course, to respond to your question I would just like to 11:41:50 9 mention the survey of the use of paroxetine in Germany by the 11:41:57 10 Zanelli study which you may have read. 11:42:03 11 And that was a survey, again, a bit like the Inman 11:42:07 12 study I mentioned yesterday, of 500 plus psychiatrists in 11:42:11 13 Germany and about 3,000 patients getting paroxetine. And 11:42:15 14 each of these patients, they asked the question what happened 11:42:19 15 in the first six weeks and what happened after that, and the 11:42:22 16 patients had to be treated for a certain minimum period of 11:42:25 17 time. So it really goes directly to the heart of your 11:42:28 18 question, do things in Germany look like things in the U.S. 11:42:33 19 And the answer is only 40 percent of the people 11:42:35 20 getting paroxetine were receiving adjunctive medications and 11:42:38 21 those adjunctive medications included a whole slew of things. 11:42:43 22 So it is obvious if somebody here is recommending that 11:42:45 23 benzodiazepines be used in conjunction with paroxetine for 11:42:50 24 this kind of depression indication, it is not clear that that 11:42:55 25 is something that physicians in Germany are automatically 1695 11:42:58 1 doing. So physicians have quite a degree of latitude about 11:43:04 2 this. 11:43:04 3 The other study was from the U.K. where it was only 8 11:43:07 4 or 9 percent of prescriptions in 13,000 patients who got 11:43:11 5 paroxetine for depression that required or were given 11:43:14 6 adjunctive benzodiazepines. 11:43:16 7 So I think that those data which are concrete and in 11:43:22 8 massive groups are far more consistent with the results of 11:43:27 9 the double-blind clinical control studies that I've been 11:43:31 10 quoting over and over where paroxetine seems to have a 11:43:34 11 remarkably beneficial effect on anxiety relative to other 11:43:43 12 SSRIs and relative to other antidepressants. 11:43:48 13 Q. Finished with the explanation? 11:43:50 14 A. Yes. 11:43:51 15 Q. My question was do psychoactive drugs affect human beings 11:43:56 16 in Germany the same as they do in this country? Now, do you 11:44:00 17 really think that answer got to the heart of the question? 11:44:03 18 A. The answer is yes. 11:44:05 19 Q. Thank you. 11:44:06 20 Until 1991 you recommended in your article with 11:44:10 21 Dr. Kapur specific future prospective tests, true or false? 11:44:19 22 A. Can you be more specific? 11:44:24 23 Q. Did you recommend that testing be done in a prospective 11:44:27 24 fashion in your 1991 article with Dr. Kapur? 11:44:30 25 A. Yes, we indicated that double-blind, prospective, 1696 11:44:34 1 randomized, control clinical trials are the best way to try 11:44:37 2 and determine the answer to the question as to the efficacy 11:44:42 3 and safety of medications. 11:44:44 4 Q. Did you recommend that in the future tests, the 11:44:47 5 prospective tests, that instead of using a HAM-D, that they 11:44:52 6 should use the Beck Suicidal Ideation Scale? 11:44:57 7 A. We indicated that the Beck Suicidal Ideation Scale has an 11:45:02 8 advantage in sensitivity which may allow one to get more 11:45:08 9 precise measures of changes in suicidal ideation. 11:45:13 10 And I discussed that yesterday. First of all, with 11:45:15 11 those thousands of patients in those databases it turns out 11:45:20 12 that the HAM-D Item 3 is sufficiently sensitive because there 11:45:24 13 are thousands of patients. In fact, in Montgomery he went 11:45:30 14 further because he used the Item 10, as you know, of his 11:45:33 15 rating scale which tested with significantly more sensitivity 11:45:38 16 than the HAM-D and it showed even more striking positive 11:45:41 17 therapeutic effects for paroxetine. 11:45:45 18 Q. My question was did you recommend the Beck scale? Could I 11:45:47 19 have an answer to that question, please? 11:45:49 20 A. We did. 11:45:52 21 Q. And is the Beck scale more sensitive and refined than the 11:45:56 22 single question on the Montgomery-Asburg scale? 11:45:59 23 A. It is not a single question. It is an item that can be 11:46:03 24 scored from zero to 7. So -- with anchor points telling you 11:46:08 25 if it is this level of severity, it is a 2; if it is this 1697 11:46:12 1 level of severity, it is a 4; if it is this level, it is a 6; 11:46:13 2 if nothing is there it is a zero. And you sort of get the 11:46:18 3 idea. 11:46:18 4 Q. We've all seen it. It is in evidence. 11:46:21 5 A. Fine. 11:46:21 6 Q. The thing that it has that the HAM-D doesn't have is a 11:46:24 7 place to focus on whether the person has a plan to commit 11:46:27 8 suicide, right? 11:46:29 9 A. No, that's not correct. 11:46:31 10 Q. Let's look at it, then. Let's just look. This is 11:47:15 11 Plaintiff's Exhibit 8. Let me see if I can zoom in on that 11:47:18 12 for us. Item 10 -- 11:47:24 13 THE COURT: Tell us what Plaintiff's Exhibit 8 is. 11:47:28 14 MR. VICKERY: The MADRS scale, Your Honor, the 11:47:30 15 Montgomery-Asburg Depression Rating Scale. 11:47:33 16 Q. (BY MR. VICKERY) Item 10 is the question on suicidal 11:47:36 17 thoughts, right? 11:47:37 18 A. Yes. 11:47:41 19 Q. What does number 6 say? 11:47:45 20 A. "Explicit plans for suicide when there is an opportunity, 11:47:49 21 active preparations for suicide." 11:47:52 22 Q. Does that refresh your recollection about whether the 11:47:55 23 Montgomery-Asburg scale has a place to rate for a plan for 11:47:58 24 suicide? 11:47:59 25 A. I said that all along. You asked me about the HAM-D. 1698 11:48:04 1 Q. The HAM-D doesn't have one for a plan, does it? 11:48:06 2 A. Let's put the HAM-D up. 11:48:08 3 Q. I will in a minute. But does it have one for a plan? 11:48:12 4 A. You mean this? It definitely distinguishes between plan 11:48:15 5 and no plan, that's correct. 11:48:18 6 Q. Now, a few minutes ago, Dr. Mann, you testified that a 11:48:20 7 prior history of suicide attempts is a strong predictor of 11:48:26 8 future suicide risk, right? 11:48:29 9 A. We don't have strong predictors of anything, but it is 11:48:34 10 amongst the predictors that we have one of the strongest. 11:48:38 11 Q. Look at what is on this scale. Suicide attempts should 11:48:42 12 not in themselves influence this rating, do you agree with 11:48:47 13 that? 11:48:47 14 A. There's a specific reason that that's in there, and that 11:48:50 15 is that the assumption of the individuals who constructed 11:48:53 16 this scale is that suicide attempts would be recorded 11:48:58 17 separately. You don't need a rating scale to record a 11:49:00 18 suicide attempt. You can record there is or isn't a suicide 11:49:07 19 attempt. 11:49:08 20 This instrument item here is designed to determine 11:49:11 21 how severe is the suicidal ideation. 11:49:14 22 Q. Okay. We were talking about your '91 paper with 11:49:17 23 Dr. Kapur, and in addition to the Beck scale, you recommended 11:49:24 24 that they use a scale to measure akathisia, did you not, sir? 11:49:38 25 A. Where are you referring to now? 1699 11:49:40 1 Q. Sorry. I didn't think I would have to show you. Let me 11:49:43 2 get it. 11:49:58 3 MR. VICKERY: This is Plaintiff's Exhibit 51 for the 11:50:00 4 record, Your Honor. It is 803(18) material. 11:50:23 5 Q. (BY MR. VICKERY) Bear with me, Doctor, for a minute. It 11:50:26 6 is going to take me a minute to find it. 11:50:52 7 Do you have the article there, footnote 58 where you 11:50:55 8 cite Barnes? 11:50:58 9 A. I'm looking at it. What page is that? 11:51:02 10 Q. There it is. Okay. 11:51:20 11 "Future studies should incorporate ratings for 11:51:22 12 akathisia, anxiety, agitation, insomnia and other side 11:51:26 13 effects to analyze the potential contribution of these 11:51:30 14 factors to the emergence of suicidality in patients receiving 11:51:38 15 antidepressant therapy." 11:51:38 16 And the footnote 58 is to the Barnes Akathisia Scale, 11:51:39 17 isn't it, that footnote right there? 11:51:48 18 A. Yes, that was one of the scales that we suggested. And 11:51:50 19 I'm glad you brought that up because somebody actually read 11:51:53 20 this article and took our advice and did the exact study 11:51:56 21 pretty much that we recommended. I can tell you about the 11:51:59 22 results of that, if you would like. 11:52:01 23 Q. We may get to that. 11:52:03 24 The people you cite here, King and Colleagues, that's 11:52:05 25 Dr. Robert King at Yale, isn't it? 1700 11:52:09 1 A. Robert King? I don't know. It might be. 11:52:12 2 Q. And even though you're at Columbia and there's maybe a 11:52:16 3 little Ivy League rivalry there, those are pretty respectable 11:52:22 4 folks down at Yale, aren't they? 11:52:24 5 A. Yes. We beat them in football all the time, but that has 11:52:26 6 nothing to do with our view of their science. 11:52:26 7 Q. Are they good scientists and doctors? 11:52:29 8 A. Some are, some aren't. This study was not a particularly 11:52:32 9 good study. 11:52:35 10 Q. It was a study involving children that became suicidal on 11:52:37 11 SSRI drugs, wasn't it? 11:52:40 12 A. It was a set of case reports in young people who had 11:52:43 13 obsessive-compulsive disorder and started off on very high 11:52:48 14 doses of Prozac. 11:52:50 15 Q. Now, one of the ways that you suggested -- maybe I better 11:53:01 16 put this back up. 11:53:02 17 One of the thing