Charles M. Beasley, Jr., M.D. 11/8/00   

               IN THE UNITED STATES DISTRICT COURT
                   FOR THE DISTRICT OF VERMONT
       
       JOSE G. ESPINOZA and                 )
       MINNIE T. ESPINOZA,                  )
                                            )
                         Plaintiffs,        ) 
                 v.                         ) NO.2:99_CV_393
       ELI LILLY & COMPANY,                 )
                                            )
                         Defendant.         )
       ______________________________________
       MICHAEL L. BLANCHARD,                )
       Individually and as Administrator of )    
       the Estate of ROSS ALLEN BLANCHARD,  )   
       and as Administrator of the Estate   )
       RENE MARIE BLANCHARD,                )
                                            )
                         Plaintiff,         )
                 v.                         ) NO.2:99_CV_256
       ELI LILLY & COMPANY,                 )
                                            )
                         Defendant.         )

       VIDEOTAPED
       DEPOSITION OF:    CHARLES BEASLEY, JR., M.D.
       
       DATE AND TIME:    November 8, 2000, 3:51 p.m. 
       
       PLACE:            Offices of Baker & Daniels
                         300 North Meridian St., Suite 2700
                         Indianapolis, IN  46204
       
       ON BEHALF OF:     Plaintiffs
       
       PURSUANT TO:      Notice and Federal Rules of Civil
                         Procedure
       
       BEFORE:           Dorothy E. Huffman, RPR, NP
       
                     Charles M. Beasley, Jr., M.D. 11/8/00   

                           APPEARANCES
       
              Charles M. Beasley, Jr., M.D. 11/8/00   

                              INDEX
       
       DIRECT EXAMINATION
       
            Questions by Mr. Vickery                       5
       
       CROSS_EXAMINATION
       
            Questions by Mr. See                         115
       
       REDIRECT EXAMINATION
       
            Questions by Mr. Vickery                     116
       
       RECROSS_EXAMINATION
       
            Questions by Mr. See                         119
       
       RE_REDIRECT EXAMINATION
       
            Questions by Mr. Vickery                     120

                             EXHIBITS
       
       Plaintiff's      Description                     Page
       
          1.   Dr. Beasley's handwritten notes re:
               meeting with outside consultants           49
       
          2.   Memo, Mr. Haski to Dr. Weinstein, 
               w/encl., Ltr., Parker to Weinstein
               8/24/90                                    76
       
          3.   Ltr., Clayton to Beasley, 8/24/90          
               w/encl.                                    78
       
          4.   Ltr., Mann to Beasley, 8/17/90             97
       
          5.   Graph, Prozac Suicidality Reports         108

13            QUESTIONS BY MR. VICKERY         

14               Q.   State your name, please.

15               A.   My name is Charles M. Beasley, Jr.

16               Q.   Dr. Beasley, we're here to take your 

17     deposition today in a case that has been filed 

18     against your employer.  You understand that, don't 

19     you?

20               A.   Yes, I do.

21               Q.   You've had at least one deposition 

22     taken before, haven't you?

23               A.   That's correct.

24               Q.   More than one or just the one?

25               A.   Just the one.

Charles M. Beasley, Jr., M.D. 11/8/00   

 1               Q.   And that was the deposition in the 

 2     Fentress case in May of 1994?

 3               A.   Yes.  I believe it was taken by Mr. 

 4     Smith?

 5               Q.   Right.  And I believe Ms. Zettler 

 6     asked you some questions, as well, at the end.

 7               A.   A female attorney asked me questions.  

 8     I don't recall her name.

 9               Q.   Did you give truthful testimony that 

10     day?

11               A.   Yes, I did.

12               Q.   Have you had occasion in the six plus 

13     years since that to review your deposition testimony?

14               A.   I reviewed the deposition following 

15     the giving of the deposition, but I have not reviewed 

16     that deposition since that time.

17               Q.   So you've not reviewed it in 

18     preparation of this deposition?

19               A.   No, I have not.

20               Q.   But you are confident __ you 

21     understood you were under oath that day; right?

22               A.   That's correct. 

23               Q.   And you're confident that you gave 

24     truthful testimony on that day?

25               A.   Yes, sir, I am.

 1               Q.   All right.  Well, I don't intend, any 

 2     more than may be necessary to put a few things in 

 3     context, to rehash that ground before.  I have agreed 

 4     with Mr. See to take a limited time today.  I know 

 5     the other one spanned two days, didn't it?

 6               A.   I believe it was three, but it was __

 7               Q.   It was a while?

 8               A.   It was a while, yes.

 9               Q.   Well, we've agreed to do this in three 

10     hours or less, and one of the ways that we can do 

11     that is by not rehashing things that were covered at 

12     some length there.  

13                    But I did think it's important for a 

14     jury to be able to see you and hear what you have to 

15     say.  

16                    Dr. Beasley, tell me, since May of 

17     1994, kind of update me, if you will, on any efforts 

18     that you have undertaken with respect to the issue of 

19     whether Prozac causes some patients to become violent 

20     or suicidal.

21               A.   Okay.  Actually, in November __ 

22     October or November of 1991, I was assigned to the 

23     development of a different product, olanzapine, and 

24     that became my primary responsibility at that point 

25     in time.

1                    And that has, in fact, continued up 

 2     until quite recently, when I have had added to this 

 3     development responsibilities for another compound 

 4     that has not yet been approved.  It's referred to as 

 5     M_glu_R2.  So I have not had direct responsibilities 

 6     for fluoxetine since that point in time: that is, 

 7     October_November of 1991.

 8                    Now, I have had some occasion to be 

 9     involved in specific fluoxetine or Prozac projects 

10     since then.

11               Q.   Let me interrupt.  Can we just call it 

12     Prozac for convenience?

13               A.   Certainly.  I'm sorry.  I tend to 

14     refer to it as fluoxetine, but I'll try to call it 

15     Prozac.

16               Q.   Okay.  I interrupted you, and I'm 

17     sorry.  I didn't mean to do that, but I just wanted 

18     to keep our terminology straight. 

19               A.   Certainly.

20               Q.   Tell me, if you would __ you were 

21     saying that you have had some assignments with 

22     respect to Prozac from October '91 to the present?

23               A.   That's correct.  One that I had was 

24     reviewing spontaneous data pertinent to the 

25     indication that we had filed for bulimia, so I've 

1     participated in a final review of those data for that 

 2     submission.

 3               Q.   Let me ask you about that one.  Did 

 4     that have anything to do specifically with the 

 5     question of whether or not this drug causes or 

 6     contributes to violence or suicide in some people?

 7               A.   No, it did not.

 8               Q.   All right.  What else?

 9               A.   The largest project that I have been 

10     involved in was a summary of the clinical trial data 

11     in depression for a possible submission of an 

12     application in Japan.  I have had other experience 

13     with the development of this next drug that I was 

14     working with in terms of dealing with Japanese 

15     regulatory authorities and our Japanese colleagues, 

16     and that's why I was asked to do that project.

17               Q.   Was that just for the indication of 

18     depression?

19               A.   That was specifically for the 

20     indication of depression.  There was some 

21     consideration given to whether we should prepare 

22     materials for obsessive_compulsive disorder and for 

23     bulimia, but none of the materials were actually 

24     developed to summarize the clinical trials that were 

25     done around those indications.

1               Q.   In approximately what year did you do 

 2     that?

 3               A.   That began approximately two years ago 

 4     and ran approximately one year.

 5               Q.   So from '98 to '99 time frame?

 6               A.   That's correct.

 7               Q.   Did any of those analyses focus on the 

 8     issue of Prozac and suicide/violence?

 9               A.   No, not specifically, they did not.

10               Q.   Incidentally, does Prozac have a 

11     different biological effect on Asian people?

12               A.   Well, that is something that is 

13     currently being studied.  To the best of our 

14     understanding, it does not.  We have conducted 

15     specifically pharmacokinetic trials: that is, how the 

16     drug is metabolized in Japanese people and do not see 

17     an indication that it is handled in any other way.

18               Q.   Have you done any randomized clinical 

19     trials to determine its efficacy in Japanese people?

20               A.   One trial is currently underway in 

21     Japan looking at __ it is a randomized clinical 

22     trial.

23               Q.   Specifically, to study the hypothesis 

24     that it would be an effective antidepressant?

25               A.   That's correct.

1               Q.   Now, those are two things since 

 2     October of '91, and obviously a third one is in May 

 3     of 1994 you had to give a two_ or three_day 

 4     deposition, mainly about what you had done in the 

 5     past.  Anything else since October of 1991 to the 

 6     present with respect to Prozac?

 7               A.   There was a project that I got called 

 8     into very late on a Friday afternoon to attempt to 

 9     evaluate the potential serious overdose amount 

10     associated with fluoxetine in a child or a pediatric 

11     population.  This was around the issue of, how much 

12     Prozac could be placed in a nonchildproof package 

13     versus how much should be placed in a childproof 

14     package.

15               Q.   How long was your work on that issue?

16               A.   It extended over a weekend.

17               Q.   And were you just analyzing existing 

18     databases?

19               A.   Yes.  We had a number of adverse event 

20     reports that were available to us, and that was the 

21     basis for this looking at these adverse event reports 

22     and, when available, the doses of Prozac that had 

23     been taken.

24               Q.   Approximately, when was that work 

25     done, Dr. Beasley?

 1               A.   That was probably approximately a year 

 2     and a half ago, I believe.

 3               Q.   All right.  So roughly, 1998 or maybe 

 4     early '99?

 5               A.   It would have had to have been very 

 6     early '99, I believe, if it occurred in '99.

 7               Q.   At that point in time, did Prozac have 

 8     any indication in this country for pediatric use?

 9               A.   I do not believe that it had an 

10     indication for pediatric use.

11               Q.   Had there been any clinical trials 

12     seeking to study its efficacy and safety in pediatric 

13     populations in this country?

14               A.   I believe there had been some clinical 

15     trials conducted in the pediatric population.

16               Q.   When you were doing this analysis on 

17     metabolism of Prozac by children, did it just focus 

18     on adverse events, or did it focus on adverse events 

19     plus clinical trial data?

20               A.   Let me correct the statement, please.  

21     It was not focusing on the metabolism of Prozac.  

22     This was the extent to which any given dose on a 

23     milligram_per_weight basis was having the potential 

24     to produce a serious adverse event.

25               Q.   Let me make sure I understand you.  

 1     And I think I'm the one that used this word 

 2     metabolizing, not you.  I probably just misunderstood 

 3     when you said dose.  But was your study really more 

 4     on the function of the dose of the drug in relation 

 5     to body weight rather than in relation to the age of 

 6     the human body that was going to metabolize it?

 7               A.   That's correct.  What we were doing 

 8     was looking at adverse event reports of overdoses in 

 9     individuals.  I believe the cutoff that was used was 

10     18, but it may have been 17.  And, obviously, for 

11     some of these individuals, we had very detailed 

12     information, including the amount of overdose and 

13     their body weight.  Therefore, we were looking at the 

14     extent to which, on a dose basis where you're talking 

15     about dose on a milligram_per_kilogram basis, or dose 

16     per body weight, the extent to which those adverse 

17     events might be serious or not.

18               Q.   Was your primary concern with 

19     serotonin syndrome?

20               A.   No.  There were no specific concerns 

21     within the data.  I don't recall the __ and, again, 

22     this came out of an effort to establish appropriate 

23     amounts of medication for putting into childproof 

24     packages.  

25               Q.   Right.  

 1               A.   I believe it is the consumer safety 

 2     organization that has a criteria or a set of 

 3     guidelines that are not terribly specific, but 

 4     certainly do not focus on any one specific adverse 

 5     event in order to make this determination.

 6               Q.   Can you tell me whether children and 

 7     adolescents metabolize Prozac in the same manner and 

 8     with the same efficiency as adults?

 9               A.   I'm not familiar with the data on 

10     child metabolism of Prozac.

11               Q.   Anything else that jumps to your mind 

12     between October '91 when you went over to olanzapine 

13     and the present that has dealt with Prozac?

14               A.   Let me think.  There is one additional 

15     analysis that I was involved in around whether or not 

16     there was an increased association with mania in 

17     association with Prozac.

18               Q.   Is that something that appears in a 

19     published article somewhere?

20               A.   No, it does not.

21               Q.   What gave rise to that work?

22               A.   I believe that this was a request or 

23     an interest from the Belgian regulatory agency with 

24     regard to wording and labeling.

25               Q.   When was that done? 

 1               A.   That was probably in 19 __ probably 

 2     early 1988.

 3               Q.   '88?

 4               A.   Excuse me.  

 5               Q.   '98?

 6               A.   '98.

 7               Q.   Okay.  What was your conclusion? 

 8               A.   The conclusions were that we saw no 

 9     evidence that there was an increased association with 

10     mania, but certainly mania had been reported in 

11     temporal association with the administration of 

12     Prozac.  This was __ resulted in a change in the 

13     wording of the Belgian package insert, as I recall, 

14     but I don't recall the specifics of that wording.

15               Q.   Who asked you to do that work?

16               A.   I think one of the individuals that 

17     asked me was probably Dr. Tollefson; but, 

18     specifically, I don't recall.

19               Q.   Did he supervise that work?

20               A.   I don't recall that he specifically 

21     supervised that work, no.

22               Q.   What form did your work product take?  

23     A memorandum, or a letter, or just what?

24               A.   It actually resulted in a meeting 

25     which I attended with the Belgian regulators, and 

1     verbal discussion with them, along with European 

 2     safety monitoring individuals.

 3               Q.   Did you create some work product which 

 4     you did not share with them: in other words, for your 

 5     own purposes in talking with them, like notes, or 

 6     outline memoranda, that sort of thing?

 7               A.   Yes, I believe that there were some 

 8     charts and tables that were produced with that, not 

 9     specifically by me, but by the fluoxetine team that I 

10     was working with.

11               Q.   All right, sir.  Anything else with 

12     respect to Prozac that you can think of since October 

13     of '91?

14               Q.   That's all that I recall at this 

15     point.

16               Q.   Let's see if I can jog your 

17     recollection about one.  Do you remember in 1992 a 

18     series of meetings or events concerning a study that 

19     had been done Dr. Liu and Dr. Ko in Taiwan?

20               A.   Oh, yes.  I did __ I sat in on that 

21     meeting, yes, with Drs. Liu and Ko.

22               Q.   And did you go over to Taiwan? 

23               A.   No.

24               Q.   The meeting you sat in was here in 

25     Indianapolis?

1               A.   That's correct.  I believe one was a 

 2     psychologist and one was a psychiatrist that visited 

 3     us, yes.

 4               Q.   Was the switch from Prozac to 

 5     olanzapine __ which, by the way, is that Zyprexa? 

 6               A.   That's Zyprexa.  I'm sorry.

 7               Q.   That's okay.  Either one will do.  Was 

 8     that made at your request or the company's request?

 9               A.   That was made at the company's 

10     request.

11               Q.   What kind of medication is Zyprexa? 

12               A.   Zyprexa is a medication that's 

13     currently __ it's referred to as an antipsychotic.  

14     It's actually approved now for treatment of the 

15     condition schizophrenia and the condition of mania in 

16     the longitudinal course of bipolar disorder.  Bipolar 

17     disorder has both depressive phases and manic phases.  

18     And Zyprexa is approved for the treatment of the 

19     manic phases of that condition.

20               Q.   Are Prozac and Zyprexa used in tandem 

21     for the treatment of chronic depression?

22               A.   They are used by some individuals in 

23     this fashion in treating depression, particularly 

24     severe depression.  We currently have ongoing studies 

25     that are looking at that combination.

1               Q.   All right, but no approved indication 

 2     where your people could actually market it for that; 

 3     right?

 4               A.   No, that's correct.

 5               Q.   Now, Dr. Beasley, is 'prexa (sic) a 

 6     serotonergic medication?

 7               A.   I need to sort of understand 

 8     specifically the sort of serotonin mechanisms that 

 9     we're talking about.  It does have effects on the 

10     serotonin system.  It does what we call antagonize or 

11     block certain serotonin receptors.

12               Q.   Not the reuptake site but serotonin 

13     receptors?

14               A.   That's correct.

15               Q.   And which ones?

21               A.   It blocked the 5HT2A and the 5HT2C 

22     receptor, to some extent the 5HT3 receptor, and those 

23     are the primary serotonin receptors that it has 

24     activity on at clinical doses. 

25               Q.   We're going to come back and talk in 

1     what perhaps will seem very mundane terms to you 

 2     about serotonin and these various receptors; but tell 

 3     me now, if you would, are the 5HT2A and the 5HT3 

 4     receptors, receptors for serotonin that are generally 

 5     associated with the body's antipsychotic regulation?  

 6     In other words, that's what helps the body avoid 

 7     psychotic behavior is the 5HT2A and 5HT3 receptors? 

 8               A.   Generally, it's believed that it is 

 9     the dopamine blocking activity of the drugs in the 

10     class with Zyprexa that are responsible for its 

11     antipsychotic activity.

12               Q.   All right.  Let me come back to my 

13     question, though.  Do either of the 5HT2 receptors, 

14     the A or the C, that you mentioned, or the 5HT3 

15     receptor, have anything to do with antipsychotic 

16     behavior?

17               A.   As I understand it, we have very 

18     little data to suggest that.  The hypothesis is __ 

19     and let me clarify __ that the 5HT2 receptors may be 

20     involved in what we call the negative symptoms of 

21     schizophrenia.  These are not your psychotic 

22     symptoms.  The psychotic symptoms I would think of as 

23     the delusions, the hallucinations, or very, very 

24     bizarre behavior.

25               Now, within this condition of schizophrenia 

1     there are another set of symptoms that we don't 

 2     classically refer to as psychotic, but they're very 

 3     important in the disease, and these are what we call 

 4     negative symptoms.  They're apathy, poor self_care, 

 5     etc.  So they go as part of this disease.  And it is 

 6     the belief that the antagonism of these serotonin 

 7     receptors are important in treating those aspects of 

 8     schizophrenia.

 9               Q.   All right.  We'll come back to that, I 

10     promise, because if we don't, none of that will make 

11     any sense to a jury, but we'll come back and put it 

12     in context.  

13                    Back for a minute to sort of updating 

14     me, if we may, from your May 1994 deposition, have 

15     you discussed with anyone in your company this issue 

16     of, does Prozac cause some patients to become violent 

17     or suicidal, since your May 1994 deposition? 

18               A.   I cannot recall any specific detailed 

19     discussion of this within the company with any 

20     specific individual.  

21               Q.   All right.

22               A.   My feeling is that they have occurred, 

23     but not in in_depth specific recollection.

24               Q.   Sure.  I mean it's an issue that you 

25     worked a great deal on in the '90 to '92 time frame; 

1     right?

 2               A.   That's correct.

 3               Q.   And so it would be logical that from 

 4     time to time you would have conversations with 

 5     different ones of your colleagues about that issue?

 6               A.   That's right, individuals who were 

 7     continuing to work on Prozac.

 8               Q.   Have you had any discussions about the 

 9     issue with Dr. Wheadon since he left Lilly?

10               A.   I cannot recall any specifically.  I 

11     have certainly seen Dr. Wheadon on probably two or 

12     three occasions.  I have talked to him on the phone 

13     at least once, I feel fairly certain, but I can't 

14     recall specific conversations with him.

15               Q.   All right.  I mean you and he aren't 

16     big social friends that get together for some reason?

17               A.   No, David and I were not what I'd 

18     characterize as close.  We would occasionally have a 

19     common dinner together, or something, but we weren't 

20     friends that saw one another frequently.

21               Q.   Well, you and I know, that's because 

22     he went to the wrong Ivy League school, so what can 

23     we say?

24                    One thing you didn't mention in 

25     updating is, I believe in '94 or '95 you were a 

1     co_author, along with Dr. Tollefson, of a paper that 

 2     involved a meta_analysis of the OCD database, 

 3     clinical database, with respect to this issue.  Do 

 4     you recall that?

 5               A.   I believe that the OCD database was __ 

 6     one of the co_authors that I recall would be Dr. 

 7     Wheadon.  And those were analyses that were actually, 

 8     if I'm recalling the correct paper, basic analysis of 

 9     the OCD data, those were analyses that were done in 

10     this '91 time frame and only later published.

11               Q.   I see.  And were they meta_analyses?

12               A.   Yes, in the sense that we had two 

13     studies that were available.  Now, those two studies 

14     were actually conducted identically under the same 

15     protocol.  They were prospectively separated into two 

16     studies.  So those were the bases of the analysis. 

17               Q.   That makes the meta_analysis a little 

18     bit easier than when you're trying to do, as you did, 

19     with the clinical trials for depression and look at 

20     protocols that were done under different scenarios, 

21     doesn't it?

22               A.   I'm not sure I would characterize it 

23     as any more easy or any more difficult; it was simply 

24     that there were only two that we had to consider __ 

25     smaller database.

1               Q.   Whereas you used, I believe, 17 

 2     databases in your meta_analysis of the depression 

 3     trials?

 4               A.   That's correct.  There were available 

 5     at that point in time that that analysis was 

 6     performed, 17 well_controlled randomized clinical 

 7     trials.

 8               Q.   Now, let's talk about what you mean by 

 9     that.  Do you mean by that, that 17 well_controlled 

10     randomized clinical trials are those in which there 

11     is a placebo control arm of the study? 

12               A.   No.  There was at least one control 

13     arm.  In some cases it was placebo; in some cases it 

14     was a tricyclic antidepressant, and in some cases it 

15     was both a tricyclic antidepressant and placebo. 

16               Q.   How about the 80_plus clinical trials 

17     that you did not analyze in your meta_analysis?  What 

18     was wrong with those?

19               A.   Those studies did not have a control 

20     group, so any time that we address a question 

21     scientifically, we ask about a comparison between 

22     Treatment A and Treatment B, and one of the 

23     principles of appropriate combining of studies is 

24     that you have to have within those studies all of the 

25     treatment arms that you're interested in evaluating 

1     when you make the combination of studies.

 2                    So, if you're going to look at 

 3     Treatment A, and Treatment B, then all the studies 

 4     that you combine to look at Treatment A and Treatment 

 5     B must contain Treatment A and Treatment B.

 6               Q.   Okay.  Why would the company sponsor 

 7     80 or more studies that did not have controls?

 8               A.   Well, there were a number of things 

 9     being addressed __ and I guess I should say I'm not 

10     exactly sure that I agree with the number 80.  There 

11     was some number of trials.

12               Q.   All right.  I just got that from your 

13     deposition that said __ your prior deposition said 

14     that there had been over a hundred clinical trials 

15     and you used 17 for the meta_analysis, and that's how 

16     I figured there were about 83 that were not included 

17     in your meta_analysis.

18               A.   Okay.  I was about to characterize __ 

19     first of all, some of these studies __ I think it's 

20     fairer to call them studies than clinical trials __ 

21     are the pharmacokinetic trials.  A lot of the total 

22     number of studies consist of giving Prozac in very 

23     limited fashion to individuals who do not have any 

24     psychiatric disorder to study the metabolism of the 

25     drug. 

1               Q.   Healthy volunteers?

 2               A.   Healthy volunteers.  

 3               Q.   All right.

 4               A.   That's correct.   So that's a set of 

 5     the studies, a large set of the studies.  There were 

 6     also two clinical trials that specifically addressed 

 7     different ways of administering Prozac.  For example, 

 8     is it better to give it in the evening, or is it 

 9     better to give it in the morning?  Are there any 

10     detectable differences?

11               Q.   Or twice a day, even?

12               A.   Or twice a day.  Those are the sorts 

13     of things that you would have see done to have 

14     nonalternative comparator studies.

15               Q.   All right.

16               A.   There were also additional studies.  

17     We had what we called, what were generally referred 

18     to as "compassionate use studies."  These were 

19     studies where varying mechanisms that the Food and 

20     Drug Administration allows for patients to receive 

21     treatment with a new, potentially new, alternative 

22     medication as it's approaching approval prior to 

23     approval when these are cases of severe depression 

24     that have not responded to

25               Q.   Let me __

1               A.   __ other treatments. 

 2               Q.   I'm sorry.  I violated one of my own 

 3     rules here.  I never want to interrupt you if I can 

 4     help it.

 5               A.   I'm sorry.

 6               Q.   It was my fault.  Let me follow up on 

 7     that compassion use question for a minute.  It was on 

 8     that basis that you excluded 76 out of 97 of the 

 9     actual suicides that had happened in the studies you 

10     were looking at when you did the meta_analysis of 

11     that issue in 1990_91; isn't that true?

12               MR. SEE:  Let me object because the 

13     question assumes a fact that is not in evidence, so I 

14     object to the form of the question.

15                    Dr. Beasley, you can go ahead and 

16     answer the question.

17               A.   Well, first of all, I believe the 

18     reference there correctly would be to suicide 

19     attempts, and not to actual tragically completed 

20     suicides.

21               Q.   BY MR. VICKERY:  You may be right.  

22     Without pulling the document out, which I can do if 

23     we need to __ 

24               A.   Okay.

25               Q.   I may have misspoke.  But you know 

1     what I'm talking about.  There were 97 serious 

 2     suicide events, be it an attempts or completed 

 3     suicides; and when you analyzed those for purposes of 

 4     making a submission to the FDA, you excluded 76 out 

 5     of 97.  Do you recall doing that?

 6               A.   Well, again, from the specific 

 7     meta_analysis they were __ these events __ and I'm 

 8     not certain that they were just in the meta_analysis, 

 9     because we discussed a number of other clinical 

10     trials.  I believe that the majority of these were in 

11     the compassionate use clinical trials were excluded 

12     specifically from the meta_analysis, which was really 

13     only one component of the submission to the Food and 

14     Drug Administration.

15                    Again, these patients were of somewhat 

16     different character than had been included in the 

17     clinical trials, in that they had to have failed 

18     multiple prior treatments with other alternative 

19     available antidepressants.  They were therefore 

20     potentially more seriously and more chronically 

21     depressed.  Although some of them did respond to 

22     Prozac, there certainly was no guarantee, given that 

23     they had failed multiple other medications, that they 

24     would respond.

25               Q.   Specifically, do you recall omitting 

1     76 out of the 97 serious suicidal events in your 

 2     analysis?

 3               MR. SEE:  I object.  The question was just 

 4     asked and just answered.

 5               MR. VICKERY:  No, it hasn't been answered.  

 6     Answer that specifically for me.

 7               MR. SEE:  You may answer it again, Dr. 

 8     Beasley.

 9               A.   We excluded specifically from the 

10     meta_analysis the inclusion of noncontrolled clinical 

11     trials.  Therefore, the 76 patients were not included 

12     specifically within the account of acts for the 

13     meta_analysis.

14               Q.   BY MR. VICKERY:  All right.  And the 

15     76 were not included because they were in 

16     compassionate use studies; right?

17               A.   Not because they were in compassionate 

18     use studies, but because of the nature of the 

19     compassionate use studies.  There was no appropriate 

20     __ there was no control.

21               Q.   Were all 76 in compassionate use 

22     studies?

23               A.   I cannot recall specifically if all 76 

24     were or were not.

25               Q.   To the best of your recollection, were 

1     the majority of them, if not all of them, in 

 2     compassionate use?

 3               A.   I believe that the majority were.

 4               Q.   Now, tell me this: Are the people that 

 5     are in the compassionate use studies any sicker than 

 6     the people that are getting Prozac in real life?

 7               A.   I have no way of judging the spectrum 

 8     of depression in which psychiatrists do or do not use 

 9     Prozac at this point in time.  Those individuals 

10     would certainly be candidates for receiving the 

11     medication today. 

12               A.   Right.  In other words, the clinical 

13     database that you had meta_analyzed was one in which 

14     patients who were at serious suicidal risk were 

15     excluded from the studies in the first place; right?

16               MR. SEE:  Objection: the question assumes a 

17     fact that is not in evidence, so I object to the 

18     form.

19                    You may answer, Dr. Beasley.

20               A.   Not entirely.  There were, in fact, 

21     two studies that were included in the meta_analysis 

22     that began as in_patient studies, and they had no 

23     exclusion whatsoever for a patient even being 

24     considered acutely suicidal.  And there was certainly 

25     a substantial amount of suicidal ideation present 

1     across all of these studies.

 2               Q.   BY MR. VICKERY:  In the other 15 

 3     studies that were included in your meta_analysis, is 

 4     it true that patients who were at serious suicidal 

 5     risk were excluded?  That was one of the exclusionary 

 6     criteria in the protocol for those studies?

 7               A.   Yes, in those studies, that's correct.

 8               Q.   Thank you.  Now, when one looks at the 

 9     check list for indications for Prozac, is suicidal 

10     risk one of the diagnostic criteria for depression 

11     and, therefore, something that you would typically 

12     check off in deciding to give Prozac?

13               A.   I believe that the criteria states 

14     suicidal ideation is the diagnostic criteria.

15               Q.   So, if somebody is thinking about 

16     suicide, then that __ and your company tells doctors, 

17     "You think about giving them Prozac"; right?  I know 

18     that's oversimplifying it, but that's one of the 

19     eight things that doctors look for in order to make a 

20     diagnosis for which the appropriate treatment will be 

21     Prozac, isn't it, Dr. Beasley? 

22               A.   Yes.  Characterized as one __ 

23     actually, it turns out there are a total of __ there 

24     are nine primary classification points, but amongst 

25     those nine, there actually happens to be a total 17 

1     behaviors and/or forms of thinking that requires five 

 2     of those to be present to make the diagnosis.  And 

 3     suicidal ideation is certainly one of them.

 4               Q.   Okay.  Now, let's back up, if we may.  

 5     What have you done to prepare yourself for the 

 6     deposition today?

 7               A.   I had meetings with counsel during the 

 8     week before my traffic accident __

 9               Q.   Right.

10               A.   __ interspersed between doing my other 

11     duties.  I would say probably two hours to three 

12     hours on a day or two and less on others.

13               Q.   Did you review any documents in 

14     preparation for your deposition?

15               A.   No, I did not.

16               Q.   Did you do any rehearsal sessions with 

17     videocamera?

18               A.   I had been on videocamera previously a 

19     number of months ago, but not in immediate 

20     preparation for this deposition.

21               Q.   When you say previously, in the 

22     context of a mock question_and_answer session like 

23     we're doing here?  Did you do that a number of months 

24     ago?

25               A.   Yes.

1               Q.   For what purpose?

 2               A.   To review my presence on camera.

 3               Q.   In anticipation of having to give 

 4     testimony?

 5               A.   As I said, at the time I think there 

 6     was some anticipation that I would give testimony, 

 7     but I wound up not giving testimony.

 8               Q.   I see.  And did you review those 

 9     videos after they were done?

10               A.   For about ten minutes, yes.

11               Q.   All right.  Now, Dr. Beasley, I would 

12     like to, if we could, back up and sort of get the 

13     broad overview of your specific activities in the '90 

14     to '92 time frame that we've discussed, or '90 to 

15     late '91, with respect to the issue of Prozac and 

16     suicide or violence.

17                    Before we do that, let me ask you: 

18     Prior to January of 1990 __ and to jog your 

19     recollection, that's the month that you got the 

20     preprint of the Teicher and Cole article __ prior to 

21     that, had you ever focused on this question of 

22     whether this drug might, for some patients, create an 

23     increased risk of suicide or violence?

24               A.   I recall one conversation that I had 

25     at ATA with psychiatrists, a Dr. Norden, who related 

1     rather vaguely a number of cases that he had heard 

 2     about in which the person he was describing suggested 

 3     that there were five cases of increased suicidal 

 4     ideation in association with treatment with Prozac.

14               Q.   Approximately, when did that meeting 

15     take place?

16               A.   It would have been at an APA meeting, 

17     but __ and I believe it would have probably been the 

18     1989 meeting.  

19               Q.   Can you kind of give me some contact 

20     for that discussion?  Was he just relaying to you 

21     that he had heard about these cases, and wanted your 

22     impression, or did he want you to do something about 

23     it?  

24               A.   I don't recall the specifics of the 

25     conversation.  It occurred at APA.  It occurred while 

 1     I was at the booth, the exhibit for Prozac.  I had 

 2     some vague knowledge of Dr. Norden because he had 

 3     published some papers claiming __ making rather 

 4     extravagant claims, from my perspective, on __ in 

 5     terms of improvement in a whole host of psychiatric 

 6     conditions with Prozac, and was aware that he had 

 7     filed a use patent for Prozac for virtually every 

 8     psychiatric condition known to man. 

 9               Q.   Right.  Is this the guy that your 

10     company got into a little patent flap with this guy 

11     sometime after your conversation, didn't you?

12               A.   Again, I think I saw his article, and 

13     I think I saw something about his patent application, 

14     actually, prior to the conversation.

15               Q.   Did he ever get a patent?

16               A.   I don't know whether he did or not.

17               Q.   Okay.  Now, then, let's get into the 

18     January 1990 time frame.  I know from your prior 

19     testimony that through a sales person at MacLean, a 

20     Lilly sales rep at MacLean Hospital, your company 

21     came by a preprint copy of the Teicher and Cole 

22     article.  Do you recall that?

23               A.   That's correct; yes, I do.

24               Q.   Were you the recipient of it once it 

25     reached Indianapolis, or did it go to someone else 

1     first?

 2               A.   It certainly came to me.  I don't 

 3     recall whether it came to other people or not.  It 

 4     could have gone to other people simultaneously.

 5               Q.   How long was it between the time that 

 6     article hit your desk and the time that you and Dan 

 7     Masica were on an airplane to Boston to meet with Dr. 

 8     Teicher and Dr. Cole and Nurse Glod? 

 9               A.   I think that we probably called and 

10     made arrangements to visit probably within 48 hours.  

11     We were very interested in this paper.

12               Q.   Obviously.  You were very concerned 

13     about it, weren't you?

14               A.   I would say that we were, again, very 

15     interested in the whole issue.  And this is 

16     incredibly important to patients.

17               Q.   If there is a risk, however small 

18     percentagewise it is, but if there is a risk that 

19     this drug would cause some patients to become violent 

20     or suicidal, you wanted to know about it, didn't you?

21               A.   Yes.

22               Q.   And here were two very respected 

23     Harvard physicians publishing a paper in a 

24     peer_reviewed respected journal suggesting that 

25     possibility; correct?

1               A.   As I recall the content of Dr. 

 2     Teicher's paper __ and, again, I did not read that 

 3     paper in preparation for this deposition __ but my 

 4     recollection is that what Dr. Teicher was describing, 

 5     and Dr. Cole, as well, as one of the co_authors,

 6     was a very specific form of suicidal ideation that 

 7     occurred in patients.  And that was what was being 

 8     suggested as being observed: that it was suicidal 

 9     ideation __ I recall my characterization __ was of 

10     extreme increase.

11               Q.   And iatrogenic, wasn't it, in their 

12     view?

13               A.   They were suggesting the potential 

14     that it be caused by Prozac in their paper.  It had 

15     the characteristics of being severe, extreme in its 

16     increase in amount, that it involved violent ideas on 

17     methods of suicide, and that it was what we would 

18     describe as being dysphoric or egodystonic, meaning 

19     patients didn't like having the idea.  It didn't 

20     really fit with what part of them wanted to do, or 

21     what they really expected to do with themselves.  It 

22     seemed foreign to them.

23               Q.   Almost as if they were being 

24     controlled by an alien, or something like that?  I'm 

25     searching for a metaphor to describe egodystonic.  

1               A.   Not what they really wanted to be 

 2     experiencing.

 3               Q.   So something that's just contrary or 

 4     foreign to their personalities and their being?

 5               A.   Contrary to their intentions or their 

 6     general ways of thinking, and that they don't want.

 7               Q.   But did they seem sort of powerless to 

 8     control it?

 9               MR. SEE:  I'm going to object to the form 

10     of the question.  Are you asking what Dr. Teicher 

11     wrote in his article?

12               Q.   BY MR. VICKERY:  The phenomenon that 

13     Teicher and Cole observed and wrote about, did you 

14     understand it to be one where, not only did these 

15     patients have this intense, violent suicidal ideation 

16     that was foreign to them, but was also something that 

17     was beyond their control?

18               A.   I didn't have that conception of this 

19     phenomenon at the time.  What I had, and what I still 

20     have, is identifying these four aspects of the 

21     phenomenon as I read the paper.

22               Q.   Which are what?

23               A.   Which are the incremental or quantal 

24     increase in severity.

25               Q.   Okay.  

1               A.   The obsessional nature seems to __ 

 2     these ideas seem to intrude, I think is another word 

 3     to describe that.  

 4               Q.   Okay.

 5               A.   That the thoughts were of a violent 

 6     nature.

 7               Q.   Okay.

 8               A.   And then, finally, the most difficult 

 9     term to describe is that they were egodystonic __ 

10     they wee egodystonic and/or discord.  They were not 

11     wanted __ did not seem to fit with the rest of the 

12     ways that the individual patients were thinking, 

13     certainly not something they were truly planning to 

14     do.

15               Q.   Foreign to the person, is that what 

16     you're saying?

17               A.   Foreign to the person and also not a 

18     true intent of the person.

19               Q.   Now, if that phenomenon is a real 

20     phenomenon, it is something that is unique and 

21     distinct from the normal suicide that you as a 

22     psychiatrist learned about to be a risk of 

23     depression, isn't it?

24               A.   I'm sorry.

25               Q.   Let me rephrase it; it was poorly 

1     phrased.  Would it be very rare for you to see this 

 2     phenomenon with these four distinct aspects that 

 3     you've mentioned in a patient who merely had 

 4     depression?

 5               A.   Certainly, suicide can take many __ 

 6     suicidal ideation can take many, many forms in human 

 7     beings that have this ideation.  You can have a range 

 8     of severities.  And, in fact, suicidal ideation can 

 9     change abruptly in terms of its severity.

10               Certainly, from writing the paper, Dr. 

11     Teicher and Dr. Cole felt that this was fairly 

12     unique.

13               We had certainly not heard previous 

14     descriptions of this other than possibly Dr. Norden's 

15     description, which may have been __ in fact, we could 

16     not identify __ he could have heard of Dr. Teicher's 

17     paper.  I don't know.  

18               Q.   Sure.

19               A.   But they characterized it as fairly 

20     unique.

21               Q.   You have studied __ in addition to 

22     their paper, you have studied, both as part of your 

23     psychiatric residency at Yale and as a part of your 

24     work at Lilly, the phenomenon of suicide as a risk of 

25     depression, haven't you?

1               A.   Yes, suicide is more common and may 

 2     occur in depression.  

 3               Q.   Okay.

 4               A.   So depression is a risk factor for 

 5     suicide, and suicidal ideation is certainly very 

 6     common within the depressed patient population.

 7               Q.   Now, is a suicidal ideation that has 

 8     these four distinct aspects that you just ticked off 

 9     for me something that is commonly seen in depression, 

10     based on either your clinical experience, your 

11     education, or your review of the literature?

12               A.   I would not view this as particularly 

13     common.

14               Q.   All right.  Now, did you discuss with 

15     Dr. Teicher and Dr. Cole the fact that this 

16     phenomenon had occurred in temporal relationship to 

17     the patient's ingestion of Prozac?  

18               A.   Well, it was __ from their paper, they 

19     certainly stated that this occurred in temporal 

20     association.

21               Q.   And by that we just mean that it 

22     occurred __ 

23               A.   __ while they were taking Prozac.

24               Q.   __ while they were taking it, and 

25     shortly after either they started taking it or had a 

1     dose increase; right?

 2               A.   I think they described what I would 

 3     characterize as a fair __ if I recall it correctly, I 

 4     think it was one to seven weeks was the temporal 

 5     course that they described. 

 6               Q.   And that would be a period of time 

 7     before the blood plasma concentrations of Prozac 

 8     reached their point of equilibrium or therapeutic 

 9     level in the blood, wouldn't it?

10               A.   We generally believe that on an 

11     average __ and, again, this can vary from patient to 

12     patient __ that the time to reach equilibrium, as you 

13     could call it, may be up to five weeks.  It can be 

14     less than that.

15               Q.   Okay, sir.  Now, did they either __ 

16     did you learn either from their paper or discussions 

17     with them any biologically plausible explanation of 

18     just how this could be happening?

19               A.   No, we didn't __ at least to my  

20     recollection, I don't recall a discussion of 

21     biological mechanisms, and I don't believe that there 

22     was one included in the paper.  

23               Q.   Have you in your study of this issue 

24     at any time focused on possible biological 

25     explanations?

1               A.   We've certainly given consideration to 

 2     serotonin and the data with regard to a relationship 

 3     between serotonin and aggression or violence. 

 4                    Our general consideration has been 

 5     that, in fact, augmentation of serotonergic 

 6     transmission reduces aggression and violence.

 7               Q.   I want to talk to you about that.  

 8     Let's kind of have our serotonin discussion now, if 

 9     we may, to put it in context.  Is serotonin typically 

10     called 5HT?

11               A.   Yes, that's the abbreviation for 

12     serotonin.

13               Q.   What is serotonin?

14               A.   Serotonin is a chemical that acts __ 

15     it's what we call a neurotransmitter: in other words, 

16     it transmits signals from neuron to neuron in the 

17     brain in certain anatomical pathways.  Neurons are 

18     brain cells. 

19               Q.   It's not just found in the brain; it's 

20     found in the intestinal tract, isn't it?

21               A.   It's found in __ all throughout the 

22     body.

23               Q.   And what is the principal metabolite 

24     of serotonin?  

25               A.   The __ I do not recall the principal 

1     metabolite.

 2               Q.   Let's see if I can jog your 

 3     recollection.  Is it 5HTI __

 4               A.   __ AA.

 5               Q.   __ AA? 

 6               A.   That's correct.

 7               Q.   And by metabolite do we mean that 

 8     substance into which serotonin becomes?

 9               A.   When serotonin is broken down, yes. 

10               Q.   Now, Prozac blocks the reuptake site 

11     for serotonin; correct?

12               A.   That's correct.

13               Q.   Is the reuptake site a metabolic 

14     pathway?

15               A.   I would not characterize it in that 

16     fashion, and I do not recall ever hearing anybody 

17     characterize it in that fashion.  By "metabolic 

18     pathway," I would understand you to mean something 

19     involved in it being chemically broken down.

20               Q.   Right, into 5HIAA?  

21               A.   Right.

22               Q.   All right.  So, when it goes through 

23     the reuptake site, it really just kind of goes back 

24     to carry a message again: in other words, it goes 

25     back into the cell, back into the neuron, ready to 

1     carry another message to another receptor; right?

 2               A.   That's correct.  It may be __ some of 

 3     it may be broken down within the cell, because there 

 4     are metabolic pathways within the cell, but a good 

 5     bit is repackaged or rereleased.

 6               Q.   Now, you were talking about some 

 7     studies about the relationship of serotonin to 

 8     violence or suicide.  Are you discussing generally 

 9     the work of Frank Aid (phonetic) or Ide (phonetic), 

10     however you pronounce that name, A_Y_D?

11               A.   I was thinking more of studies of Emil 

12     Coccaro. 

13               Q.   All right.  And can you tell me, just 

14     generally, what those studies showed?

15               A.   Those studies have showed that 

16     augmentation of serotonergic transition with 

17     serotonin uptake inhibitors will generally reduce 

18     aggression/violence in individuals who have 

19     predisposition to these things, based on the presence 

20     of what we call character disorders or character 

21     pathology or personality disorders. 

22               Q.   Are you aware of the published studies 

23     where scientists looked at the levels of 5HTIAA, the 

24     metabolite of serotonin, in the cerebral spine and 

25     the central nervous system of people who had 

1     committed suicide?  

 2               A.   Yes, I believe that some of the first 

 3     work __ some of that first work is Marie Asburg's 

 4     work.

 5               Q.   Right.  And what was found was that 

 6     people who had committed suicide had a low level of 

 7     5HTIAA; correct?

 8               A.   That's my understanding of the work.

 9               Q.   So that there was a distinct 

10     association between low 5HTIAA and suicide in the 

11     scientific literature; correct?

12               A.   That's correct.

13               Q.   And is that the sort of postulate on 

14     which companies like yours said, "Hey, if we can 

15     increase serotonergic activity, maybe we can treat 

16     depression"? 

17               A.   Again, I am uncertain how Lilly, when 

18     they decided to develop this particular compound, 

19     what the basis of that happened to be.  So I can't 

20     speak to any specific company's rationale.  

21                    Certainly, I believe that Marie 

22     Asburg's work was part of what led to an interest in 

23     serotonin and depression. 

24               Q.   Isn't that work really the thing that 

25     is the foundation __ I know you didn't have personal 

1     knowledge because you didn't come until '87 or '88 __ 

 2     but isn't that really the sort of scientific 

 3     foundation for the use of SSRI drugs like Prozac to 

 4     treat depression?

 5               A.   Again, I would believe, reasonably, 

 6     that that would be one of the foundations.

 7               Q.   Now, answer me this: Does Prozac cause 

 8     a decrease of 5HTIAA in animals and humans?

 9               MR. SEE:  I object to the compound nature 

10     of the question.  It's really two questions. 

11               MR. VICKERY:  All right.  I'll break it 

12     down.

13               Q.   Does it cause a decrease in 5HTIAA in 

14     human beings?

15               A.   I am unaware of specific human data 

16     with regard to __ at this point in time, right now, 

17     sitting here __ with regard to the impact of Prozac 

18     on human serotonin metabolites.

19                    There is one study out of Scandinavia  

20     that may have commented on this.  Again, I do not 

21     recall the specific nature of this.  I have reviewed 

22     this issue in the past.

23                    I am aware of animal studies where I 

24     believe the results were, in fact, mixed, with the 

25     understanding that the reduction in 5HIAA is due to 

1     increased efficiency in serotonin neurotransmission. 

 2               Q.   The point is that there are both 

 3     animal and human studies that indicate that Prozac 

 4     results in a lower level of serotonin metabolite; 

 5     isn't that true, Dr. Beasley?

 6               MR. SEE:  Objection.  That exact question 

 7     was just asked and just answered by the doctor.

 8                    Doctor, if you __

 9               MR. VICKERY:  You may answer my question.

10               MR. SEE:  __ have additional answer you may 

11     __ additional information, you may answer. 

12               A.   Okay.  As I said, I cannot speak to 

13     specifically human studies, because I just don't 

14     remember.  From the animal work __

15               Q.   I'm sorry.  Go ahead.  I'm going to 

16     find something that I hope will help jog your 

17     recollection.

18               A.   From the animal work, I am fairly 

19     certain that there are studies that suggest that it 

20     is both reduced and not reduced, with the hypothesis 

21     being that the reduction is due to increased 

22     efficiency of serotonergic transmission. 

23               Q.   Whatever causes it, if the drug 

24     results in lower 5HIAA, if it results in that, then 

25     it results in the very biological condition that was 

1     found by Marie Asburg to be associated with suicide; 

 2     isn't that true?

 3               A.   The finding of the reduced 5HIAA would 

 4     be similar.  Dr. Asburg's hypothesis and 

 5     understanding of that condition is that that lack of 

 6     5HIAA was due to the efficient production of 

 7     serotonin, decreased serotonergic neurotransmission, 

 8     as I understand it.

 9               Q.   But, if the bottom line result is that 

10     people who commit suicide have low 5HIAA, there is 

11     evidence out there to indicate that Prozac causes 

12     that; isn't that true?

13               MR. SEE:  Objection.  The same question was 

14     just asked and just answered.  

15                    If you have additional information, 

16     Dr. Beasley, you may answer.

17               A.   I mean I'd like to summarize my 

18     position again, which is that, as I understand Marie 

19     Asburg's work, there is a concrete finding that there 

20     is reduced 5HIAA, that it is believed that this 

21     reduced 5HIAA is because the brain is not making 

22     enough serotonin, is not having sufficient 

23     serotonergic transmission.

24                    Prozac, in fact, in some studies, has 

25     been found to reduce 5HIAA.  However, other 

1     physiological biochemical markers suggest an increase 

 2     in the efficiency of the serotonergic 

 3     neurotransmission.

 4               MR. VICKERY:  Let me ask the court reporter 

 5     to mark that as Beasley Exhibit 1 to this deposition.  

 6     I have a copy for Mr. See.

 7               MR. SEE:  Thank you.

 8                    (The reporter so identified the 

 9            document.)

10               Q.   Dr. Beasley, what we have handed you 

11     here as Exhibit 1 to this deposition has control 

12     numbers PZ 391 2020 through 2024 and they are a 

13     series of handwritten notes.  Do you recognize the 

14     handwriting?

15               A.   I would say that the handwriting is 

16     mine.

17               Q.   All right, sir.  Now, why don't you 

18     take a minute to glance over them, because I don't 

19     want to ask you something until you've had a chance 

20     to refamiliarize yourself with it.   

21                    Do you need time to go off, or do you 

22     just want to glance through and wait for my question, 

23     sir?

24               A.   I could take a couple of minutes to 

25     read it, if that's __

10               Q.   BY MR. VICKERY:  Dr. Beasley, at the 

11     break, you told me you do not believe the final page, 

12     391 2024, is in your handwriting?

13               A.   That's correct.

14               Q.   But the other four pages are?

15               A.   Yes, they are.

16               Q.   Now, are these notes that you took in 

17     1994 when your company hired a number of 

18     distinguished outside consultants to advise you with 

19     regard to the issue of whether the Teicher_Cole 

20     phenomenon was a real thing or not?

21               A.   I believe that these are __ and it 

22     took me a moment to recognize what these are.  I 

23     believe that these are notes that I took __ excuse me 

24     __ during a meeting with outside consultants that 

25     would have probably taken place in early to mid __ 

1     probably late 1990 or early 1991.

 2               Q.   All right.  And those outside 

 3     consultants included Gary Tollefson, Jan Fawcett, Joe 

 4     Rosenbaum, and Dr. Winokur; right?

 5               A.   Yes.

 6               Q.   Over on the page that has 2023, the 

 7     last page __ 

 8               A.   Yes.

 9               Q.   Do you see there where you wrote (as 

10     read): Animal data, paradoxical effect, depletion, 

11     decreased 5HIAA, and then comma, 5HT1A?

12               A.   That's correct.

13               Q.   And is that what we were just talking 

14     about, that the animal studies had shown that, 

15     paradoxically, Prozac causes a decretion (sic) and a 

16     depletion or decrease in the level of 5HIAA in 

17     animals?

18               A.   No, I would not characterize that as 

19     paradoxical.  We would expect a decrease in 5HIAA if 

20     we were having more efficient serotonergic 

21     neurotransmission. 

22               Q.   Then why did you write "paradoxical 

23     effect"?

24               A.   Because __ and, again, I do not recall 

25     the details of this specific meeting.  It could well 

1     have been that there was a discussion of this as a 

 2     possible paradoxical effect by one of the 

 3     participants in that meeting.  There was certainly a 

 4     great deal that was discussed.

 5               Q.   If one were going to increase the 

 6     overall level of serotonin in the body, you would 

 7     expect that both the level of serotonin and its 

 8     metabolite would increase; correct?

 9               A.   That depends upon whether the 

10     serotonin was being released from vesicles and 

11     available for metabolism.  You've got to have the 

12     stuff available to the metabolic enzymes to produce 

13     5HIAA.  If you've got very, very, efficient 

14     transmission, then you're going to be releasing less, 

15     you're going to be making less 5HIAA.

16               Q.   The normal human being has about 10 

17     milligrams of serotonin in their body, don't they?

18               A.   I would not know the specific amount 

19     of serotonin.

20               Q.   Do you know that the amount of 

21     serotonin that a person has in their entire body is 

22     less than the amount of Prozac that they take once a 

23     day if they're on a 20_milligram dose?

24               A.   Again, I don't know the amount of 

25     serotonin in the average human body.

1               Q.   All right.  Do you recall now, having 

 2     read this, as to why it was that anyone was making 

 3     this observation and why you were writing it down, 

 4     about the decrease in 5HIAA?

 5               A.   Yes.  These are certainly potentially 

 6     important issues to consider in the entire domain of 

 7     this hypothesis.

 8               Q.   Because of the Asburg work?

 9               A.   Because of the Asburg work.

10               Q.   Now, you wrote after that, "5HT1A.  

11     Why did you do that?

12               A.   That is a serotonin __ that is one of 

13     the serotonin receptors that some data suggests also 

14     alters during treatment with Prozac __

15               Q.   Does __

16               A.   __ along with other serotonin 

17     receptors.

18               Q.   The __ in other words, the 5HT1A, that 

19     is a receptor that receives the message that the 

20     little __ the little serotonin molecule is carrying; 

21     right?

22               A.   Yes.

23               Q.   And that receptor is one that, 

24     generally speaking, is thought to have a lot to do 

25     with anxiety, with sleep patterns, with depression 

1     and mood, isn't it?

 2               A.   Well, I think that the majority of the 

 3     5HT1A and 2 receptors are considered to be important 

 4     in these areas.

 5               Q.  All right.  Now, let's identify how 

 6     many there are.  There's a 5HT1A, and 1B only in 

 7     animals; right?

 8               A.   I think __ the number changes sort of 

 9     weekly.  I think there are about 15 that have been __ 

10     15 to 17 __ that have been identified.

11               Q.   And some of them regulate such things 

12     as appetite or sexual function, and others regulate 

13     such things as mood and body movements __ I mean they 

14     affect a whole range of human emotions and 

15     physiology, don't they?

16               A.   Certainly, serotonin is involved in a 

17     lot of bodily processes.  Now, we don't know 

18     specifically, necessarily, in humans which receptors 

19     function with what specific behaviors or emotions.

20               Q.   Has your company, to your knowledge, 

21     ever conducted any kind of study to determine whether 

22     Prozac really does reduce the level of 5HIAA in the 

23     human body?

24               A.   I believe that some of the work that 

25     has been done, the basic pharmacology work, at Lilly 

1     have looked at these issues.

 2               Q.   Do you know the results?

 3               A.   I don't recall specifically.

 4               Q.   Do you know whether your company has 

 5     done any work to figure out whether Prozac actually 

 6     causes a reduction in the number of active 5HT1 and 

 7     5HT2 sites?

 8               A.   Well, I'm not sure that I understand 

 9     what you mean by "active," because it would be 

10     impossible to identify active versus inactive sites.  

11     The sites are there versus not there.

12                    I'm certain that Dr. Wahl published a 

13     number of __ there were a number of papers that came 

14     out of his laboratory that dealt with the 

15     observations in terms of number of 5HT1 and 5HT2 

16     receptors.  I don't recall the specifics of the 

17     outcome of those studies.

18               Q.   All right.  Let's look at the 

19     document, if we may, here on the first page that has 

20     the numbers 2020.  It seems, the way you set it up, 

21     that you're taking notes of comments made by the 

22     various consultants.  Is that what you were doing?

23               A.   I believe that that's what I was doing 

24     from these references to __ and seeing the names of 

25     individuals here.

1               Q.   Now, the first one is Gary Tollefson; 

 2     correct?

 3               A.   That's correct.

 4               Q.   So it says, "focus on nine cases."  Do 

 5     you know what nine cases he was talking about?

 6               A.   No, I do not.

 7               Q.   It says after that: "Possible small 

 8     number get paradox."  Was he saying that it's 

 9     possible that there is a small number of patients who 

10     have a paradoxical reaction akin to that that had 

11     been described by Teicher and Cole?

12               A.   That's my __ 

13               MR. SEE:  Let me __ let me __

14               MR. VICKERY:  Don't interrupt him, now. 

15               MR. SEE:  I'm not interrupting him, but I'm 

16     objecting.  Are you asking him what Dr. Tollefson 

17     thought __ 

18               MR. VICKERY:  I'm asking __

19               MR. SEE:  __ or what Dr. Tollefson meant?

20               MR. VICKERY:  He wrote it down.  Yes, I am. 

21               Q.   I'm asking you __ 

22               MR. SEE:  Do you understand, Dr. Beasley?  

23     He's asking you about what Dr. Tollefson thought or 

24     meant.

25               MR. VICKERY:  I object to the coaching.

 1               MR. SEE:  There's no coaching here.  Ask 

 2     the question clearly and he'll give you an answer.

 3               Q.   Why did you write down under Gary 

 4     Tollefson's name, "possible small number get 

 5     paradox"?

 6               A.   I believe that I wrote that down 

 7     because there was discussion about the possibility of 

 8     patients showing paradoxical development of suicidal 

 9     ideation in the context of this discussion.  That was 

10     certainly what Dr. Teicher suggested.

11               Q.   That's right.  And Dr. Tollefson said 

12     that that's possible that there are a small number 

13     that are having that reaction, didn't he?

14               A.   I don't recall Dr. Tollefson's 

15     specific words.  I wrote this statement, 

16     "possible small number get paradox."

17               Q.   And that was your interpretation of 

18     the precise words or comments used by Gary Tollefson 

19     on that day, wasn't it?

20               A.   Again, I can't recall what Dr. 

21     Tollefson said.  I certainly wrote this.  It was 

22     either an interpretation or something that I wrote 

23     down that was sparked by something that Dr. Tollefson 

24     said, since it's appearing under Dr. Tollefson's 

25     name.

1               Q.   And about four lines under that, it 

 2     says, "suggestion about risk relating to akathisia."  

 3     Gary Tollefson said that in that meeting, too, didn't 

 4     he?

 5               A.   Again, I can't recall specifically 

 6     what Dr. Tollefson said, sitting here today.  I 

 7     certainly wrote this under Dr. Tollefson's name.

 8               Q.   Your best recollection is, whatever 

 9     precise words he used, the message you received was 

10     that he suggested that this risk of this paradoxical 

11     relationship was somehow related to akathisia; isn't 

12     that true, sir?

13               A.   I don't recall the meeting.  From 

14     sitting here looking at these words, that __ that, I 

15     would agree with.

16               Q.   All right.  And we know from your 

17     prior testimony that one of the side effects of 

18     Prozac is akathisia, isn't it?

19               A.   First of all, I disagree with 

20     characterizing the akathisia as a side effect.  Okay?  

21     From my perspective, I do not believe that Prozac 

22     causes akathisia.  The entirety of the scientific 

23     data don't support that position.

24               Q.   Well, in your testimony __ and I'll 

25     pull it out if we need to __ but as you listed the 

1     side effects of the drug, under oath, in May of 1994, 

 2     you listed agitation and restlessness and akathisia, 

 3     didn't you, sir?

 4               A.   Again, I do not recall specifically 

 5     what I made reference to in terms of side effects.  I 

 6     would find it difficult to believe that I made 

 7     reference to akathisia as a side effect.

 8               Q.   All right.  Let's look further under 

 9     the comments that you interpreted from Dr. Tollefson.  

10     "Prospective."  He's talking there about prospective 

11     ways to go out and study this issue in the future; 

12     right?

13               A.   That's correct.

14               Q.   Now, meta_analysis of what's been done 

15     in the past is retrospective, isn't it? 

16               A.   That's correct.

17               Q.   So, prospective is looking at it going 

18     in?

19               A.   That would be further studies from 

20     that point in time, where you're talking about 

21     retrospective versus prospective.

22               Q.   You wrote here, "The agitated dp 

23     study."  What's that?

24               A.   That would have been the agitated 

25     depression study.

1               Q.   Had there been one?

 2               A.   There was certainly one conducted, and 

 3     I believe it was being conducted at that time.

 4               Q.   And was there a thought that that 

 5     study might incorporate some aspect to look into this 

 6     issue of whether Prozac causes violence or suicide?

 7               A.   Well, this was a study that Dr. 

 8     Tollefson was, in fact, conducting as a chief 

 9     investigator, as I recall.  And it is a study which 

10     would be particularly interesting in terms of 

11     addressing the hypothesis, because patients were, in 

12     fact, agitated in this study.

13               Q.   All right.  Is that what you would 

14     call an enriched patient group?

15               A.   No, I would not call it an enriched 

16     patient group; I would call it a subset of 

17     depression.  

18               Q.   All right.  Under that __

19               A.   You're looking at __

20               MR. SEE:  I'm sorry.  Were you finished?

21               A.   You're looking at a more homogenous 

22     type, subtype of depression. 

23               Q.   And that's people who have agitation 

24     as a significant component of depression.

25               A.   That's correct.

1               Q.   And that would put them at greater 

 2     risk for suicide, wouldn't it?

 3               A.   No, I do not believe that agitation 

 4     necessarily puts an individual at greater risk for 

 5     suicide.  That was certainly something that was 

 6     hypothesized about, and that's why this particular 

 7     study would be good for addressing this specific 

 8     hypothesis.  

 9               Q.   "Use suicide scales," next line under 

10     there.  What's that refer to?  The Beck scales?

11               A.   No, there was a scale that Dr. 

12     Tollefson used.  He used a scale called the ASIQ, the 

13     Adult Suicidal Ideation Questionnaire.

14               Q.   Is it something that's similar to the 

15     Beck scale?

16               A.   It __ in that it has a large number of 

17     questions, and actually their rating __ it's a very 

18     rating item associated with it __ in that sense it's 

19     similar to the Beck.

20               Q.   You know about the Beck scales, don't 

21     you?

22               A.   Yes.

23               Q.   And one of the things that you looked 

24     at when you drafted your rechallenge protocol, which 

25     we're going to talk about in a little while, is the 

1     Beck scale.  You said, "If we do this study, we'll 

 2     use the Beck scale for suicidal ideation," didn't 

 3     you?

 4               A.   No, we talked about using a 

 5     modification of the Beck scale.  We talked about 

 6     using a modification of that, which was the Miller 

 7     scale further modified.

 8               Q.   I'm going to show you the document in 

 9     a few minutes, because Exhibit C to your rechallenge 

10     protocol says the 1979 Beck scales.  Does that jog 

11     your recollection at all?

12               A.   As I recall, as it evolved, we were 

13     intending to use a scale which incorporated __ we 

14     were interested in Dr. Teicher's hypothesis __ that 

15     would have incorporated elements of this 

16     obsessionality, this violence/suicidal ideation 

17     nature, and the egodystonic disport nature of the 

18     suicidal ideation which, in fact, the Beck scale does 

19     not capture those specific components of suicidal 

20     ideation.

21                    So it was our feeling, as we 

22     progressed in this, that we needed to incorporate 

23     something that captured those elements.

24               Q.   Those unique aspects of what Teicher 

25     and Cole had described; right? 

1               A.   If we were to do a study that 

 2     specifically addressed Dr. Teicher's phenomenon.

 3               Q.   And that's because that HAM D Item 3, 

 4     with the 0 to 4 rating scale isn't really geared 

 5     toward measuring those four aspects of the types of 

 6     phenomenon as you've described them, is it? 

 7               A.   The HAM D Item 3 captures very, very 

 8     well, from my perspective, one element of those four, 

 9     and that is the substantial increase, the severity.  

10     It does not capture the other three.

11               Q.   All right.  Now, look at the page if 

12     you would, and you see under "Rosenbaum" there, the 

13     fourth line down, you wrote, suicidal dash 

14     interaction impulse relating to anxiety.  

15                    Do you recall what it was, either that 

16     Dr. Rosenbaum said or that struck you about his 

17     comments with regard to this entry?

18               A.   No, I do not, and the way that I would 

19     read these notes is that the writing was intended: 

20     impulsivity versus anxiety.  It's two separate 

21     things.  Again, that's my interpretation of my 

22     handwriting seeing it today.

23               Q.   Well, you're better qualified to 

24     interpret your handwriting than me, so __

25               A.   Okay.  It's pretty sloppy there, isn't 

1     it?

 2               Q.   It's not so bad.  Interaction impulse 

 3     __ I'm sorry __ what did you say?  What's your 

 4     interpretation of that entry?

 5               A.   Well, my best reading of this, filling 

 6     in the missing words, would be: Is there an 

 7     interaction between suicidality and impulsivity?  Or 

 8     __ I have an "and" sign here __ anxiety?  Is there 

 9     some relationship?"

10               Q.   Okay.  So that either impulsivity or 

11     anxiety, either one, could contribute to the 

12     suicidality of the patient?

13               A.   As a hypothesis.

14               Q.   All right.  Now, look over on the next 

15     page, if you would, 2022.  There are some further 

16     comments that you've written under Dr. Rosenbaum's 

17     name.  It says, "data problems _ needle in haystack."  

18     What does that mean?

19               A.   That means the general position that 

20     was, as I recall, taken by these consultants that 

21     they had not seen the Teicher phenomenon.

22               Q.   So it's a needle in a haystack?

23               A.   So it's a needle in a haystack.

24               Q.   And four or five lines down, you write 

25     there, "If exists won't find _ don't look at means _  

1     find then rechallenge."  What did you understand to 

 2     be Dr. Rosenbaum's view about, if it exists, we won't 

 3     find it?

 4               A.   If the Teicher phenomenon exists, very 

 5     specifically, with these components of 

 6     obsessionality, the egodystonic nature, the violent 

 7     nature of the ideation, we would not be able to find 

 8     that with our current analyses.

 9               Q.   Teicher and Cole themselves thought 

10     that it was a fairly rare phenomenon, didn't they?

11               A.   Well, you know, their data suggested 

12     an incidence of 3.5 percent, as I recall.  That was 

13     one of the things that we discussed at the meeting 

14     with them.  They informed us that their methods had 

15     been to query the MacLean Pharmacy with respect to 

16     how many patients had been dispensed Prozac, and they 

17     weren't really quite sure of that number.  The APA 

18     insisted upon that number for publication of their 

19     paper.  

20                    So 3.5 percent, I would not 

21     characterize that as particularly rare.  That was one 

22     of the things that was very, very difficult to 

23     understand about the publication.

24               Q.   Are you aware __ this Rosenbaum here 

25     is the same Rosenbaum of Fava and Rosenbaum fame in 

1     terms of writing an article on this issue in this 

 2     same time period, isn't it?

 3               A.   Yes, he is.

 4               Q.   And are you aware of the fact that 

 5     several people, including Dr. J. John Mann on behalf 

 6     of the ACNP and Dr. David Graham at the FDA, have 

 7     analyzed the data in the Fava and Rosenbaum article 

 8     and found that the incidence rate of 

 9     treatment_emergent suicidality on Prozac was 

10     comparable to what Teicher and Cole had observed?

11               A.   I am vaguely aware of those analyses.  

12     My recollection does not extend to the point of 

13     remembering whether that was when patients who were 

14     on combination Prozac and TCA were added in.  

15                    I think it's also important to point 

16     out that the suicidal ideation that was being talked 

17     about by Dr. Rosenbaum and Dr. Fava in that paper was 

18     not specifically this Teicher phenomenon.

19               Q.   Didn't have all the four aspects?

20               A.   Did not have all the four aspects.  

21     And certainly suicidal ideation, as I said, can be 

22     something that changes very, very abruptly.  It is 

23     quite possible for individuals to show increases in 

24     suicidal ideation during no treatment of depression 

25     or during treatment of depression.

1               Q.   Dr. Beasley, in your experience as a 

 2     scientist, you have done lots of research and writing 

 3     yourself, is one of the reasons that reputable 

 4     peer_reviewed journals include data, so that those 

 5     who are reading it can go and analyze the data for 

 6     themselves?  In other words, that they don't just 

 7     have to rely on what the author's interpretation of 

 8     the data is; they can analyze it for themselves?

 9               A.   That's correct.  It is very important 

10     to include detailed data in your publication so that 

11     those data can be used by other individuals.

12               Q.   And have you ever gone in and tried to 

13     reanalyze the data in the Fava and Rosenbaum article?

14               A.   We certainly worked with those data.  

15     I don't recall the extent of reanalysis.  We did have 

16     concern with the placing of the Prozac incidents with 

17     the Prozac plus TCA incidents and referring to that 

18     as Prozac without doing the same thing for the TCA 

19     data.

20               Q.   Dr. Beasley, was the Fava and 

21     Rosenbaum article written after these notes, Beasley 

22     Exhibit 1, after Dr. Rosenbaum met with you?

23               A.   I thought that the Rosenbaum_Fava 

24     article was written prior to this.

25               Q.   Was it written inside of Eli Lilly?

1               A.   No, it was not.

 2               Q.   Was Eli Lilly provided with a draft 

 3     and opportunity to comment on it before it was 

 4     submitted for publication?

 5               A.   We were certainly provided with a copy 

 6     of it because of our extreme interest in this issue.

 7               Q.   Before it was submitted for 

 8     publication?

 9               A.   I believe so, yes.

10               Q.   Were you permitted to make 

11     recommendations for changes to the presentation of 

12     the text or the data in that article?

13               A.   I recall our being requested to 

14     provide some additional analyses for the authors.

15               Q.   Now, Dr. Rosenbaum was paid as a 

16     consultant for the work that he was doing as 

17     referenced in those notes, wasn't he?

18               A.   I would believe that he was.

19               Q.   And was the paper, the Fava and 

20     Rosenbaum paper, underwritten in any way financially 

21     by Eli Lilly?

22               A.   I don't believe it was.

23               Q.   Do you recall personally making __ 

24     providing input from the draft stage to the final 

25     stage of the Fava and Rosenbaum paper?

1               A.   Again, my recollection is that we were 

 2     requested to provide some additional statistical 

 3     support to Dr. Fava; and I believe that that was done 

 4     so that they could present their manuscript as they 

 5     had intended to present it.

 6               Q.   And does the final manuscript reflect 

 7     that any of the statistical analysis was done, in 

 8     fact, by Eli Lilly and Company? 

 9               A.   I don't know that it does.

10               Q.   Should it? 

11               A.   From my perspective, since there was 

12     no financial support rendered and we simply provided 

13     the statistical analysis that they requested, I would 

14     not think would be necessary. 

15               Q.   You don't think that when you have 

16     scientists on Lilly payroll who are working on the 

17     Prozac team, if you will, spending their time, 

18     company time, doing work for an article that appears 

19     under the name of two academicians that that should 

20     be reflected in the paper?

21               A.   As long as we are not influencing in 

22     any way the outcome or their comments on the paper, I 

23     don't see that that would be necessary, no.

24               Q.   Why would you be looking at a draft or 

25     doing statistical analysis for them if you didn't 

1     intend to influence the outcome?

 2               A.   I can certainly tell you why we looked 

 3     at the draft.  They sent it to us voluntarily.  Our 

 4     concern was, in fact, getting this draft to the Food 

 5     and Drug Administration.  That was one of the things 

 6     that was very imperative from our perspective.

 7               Q.   Draft of the Fava and Rosenbaum paper?

 8               A.   Draft of the Fava and Rosenbaum paper 

 9     as they sent it to us.

10               Q.   I see.  Are you saying it was 

11     submitted in draft form to the Food and Drug 

12     Administration?  

13               A.   It was submitted to the Food and Drug 

14     __ and again, my recollection is not the details of 

15     how it was submitted, but I do recall that we had 

16     some discussion with Fava and Rosenbaum in terms of 

17     objection to being submitted to the Food and Drug 

18     Administration.  But, from our perspective, that was 

19     quite important to do.

20               Q.   Okay. Let's talk about this needle in 

21     the haystack for a minute.  If __ assume with me the 

22     following: that there is a study of depressed people, 

23     and just to keep our math easy, let's say there are a 

24     hundred people in the study, and 20 of them __ or 

25     let's say there are a hundred in each arm.  There is 

1     a two_arm study, a Prozac and a placebo.  And the 

 2     incidence of suicidal ideation is the same in both 

 3     groups, and it's 20 percent.  In other words, 20 of 

 4     these people in each of the arms of the study are 

 5     thinking about killing themselves.  Okay?  Are you 

 6     with me?

 7               A.   May I ask a question?  

 8               Q.   Sure.

 9               A.   Is this at the beginning of the study 

10     that they are __ 

11               Q.   Yes.  

12               A.   Okay.

13               Q.   Yes, sir.  They've __ it's just part 

14     of their depression.  Okay?  So that 20 people are 

15     thinking about killing themselves, and you give 

16     Prozac to one group, one hundred group, and you give 

17     a placebo to the other hundred; and then you measure 

18     the changes in their suicidal thinking.  All right?

19               A.   (Nods.) 

20               Q.   Now, in the Prozac group it goes down 

21     from 20 percent down to 5 percent.  Okay?  

22               A.   And this is the percentage of patients 

23     who have any suicidal __ any degree of suicidal 

24     ideation?

25               Q.   Any degree of suicidal id __ let's 

1     make it simple.  Let's assume their HAM D Item 3 

 2     rated 2.  They're thinking about it.  Okay?  But the 

 3     20 percent gets better.  That's what you would hope, 

 4     isn't it?

 5               A.   Certainly.

 6               Q.   I mean Prozac does help some depressed 

 7     people with their suicidality, doesn't it?

 8               A.   Absolutely, that's one of the things 

 9     that was very definitely shown by our paper.

10               Q.   Okay.  And I won't argue with you that 

11     it does.  And let's say __

12               MR. SEE:  I object to the comment and move 

13     that it be stricken.

14               Q.   BY MR. VICKERY:  Let's say in the 

15     placebo arm of the study that the suicidality goes 

16     down from 20 percent to 15 percent.  

17               A.   Okay.  So this is 5_percent 

18     improvement in terms of people going from some 

19     ideation to no ideation?

20               Q.   Right.  That would be what you call a 

21     placebo effect; right? 

22               A.   That's correct.

23               Q.   People were getting a sugar pill, but 

24     they think they're getting something that's helping 

25     them, and so they get better, even though there is no 

1     active medicine?

 2               A.   Although, that could also be just 

 3     cycling out of their depression, because it's a 

 4     cyclic disease. 

 5               Q.   I understand.  Now, let's say, though, 

 6     that there is a needle in that haystack, and that one 

 7     of the people in the Prozac group that wasn't 

 8     depressed before, one of the 80 who was never 

 9     thinking about it, became very actively suicidal with 

10     all four of the aspects that you've described in the 

11     Teicher and Cole phenomenon.  

12                    Now, if that happened, that's the 

13     needle in the haystack we'd never find.  That would 

14     be buried, wouldn't it?

15               MR. SEE:  I object to the question on the 

16     ground that it is an improper hypothetical, so my 

17     objection is to the form.  It assumes facts that are 

18     not in evidence, and does not provide sufficient 

19     facts to provide an answer.  

20                    Dr. Beasley, if you understand the 

21     question, you can answer it.

22               MR. VICKERY:  Now, I don't have any quarrel 

23     with your making a legal objection, Counsel, but 

24     these instructions to a witness about "if they  

25     understand" is coaching, and I'd ask you not to do 

1     it.

 2               MR. SEE:  There's no coaching here.  I 

 3     instructed Dr. Beasley that, if he can, he ought to 

 4     answer your question as fully as he's able.

 5               MR. VICKERY:  When you say, "if you 

 6     understand it," that's a cue that says, "Hey, you 

 7     know, you can get out of this by saying, 'Oh, I don't 

 8     understand your question.'"  I resent the coaching.  

 9     If you have an objection to preserve your legal 

10     record, make it.  But please don't try to coach the 

11     witness. 

12               MR. SEE:  There was no coaching done.

13               THE WITNESS:  I believe I understand the 

14     question.

15               MR. VICKERY:  All right.

16               A.   You've only described one aspect of 

17     the source of analyses that would be done in this 

18     study to look for the, quotes, needle in the 

19     haystack.  You've described an analysis of all 

20     improvements.  In other words, we're taking any 

21     patient, the likes of what you described as patients 

22     who improved completely, to go from some positive 

23     score to a zero on the Hamilton.  

24                    That's not the only sort of analysis 

25     that one would do if one is focusing on suicidal 

1     ideation.  One would also look for changes increased, 

 2     and specifically major increases, such as with the 

 3     Hamilton from 0_1, to 3_4.

 4               Q.   Dr. Beasley, I realize I've made the 

 5     example simple for the purpose of our understanding 

 6     it and communicating it.  But if the overall 

 7     incidence of suicidality goes down, but there is in 

 8     some patient a paradoxical Teicher_like phenomenon of 

 9     an increase, won't that needle be buried in the 

10     haystack?

11               MR. SEE:  Objection.  Same objection to the 

12     improper hypothetical, and the additional objection 

13     is that you just asked the same question that has 

14     already been provided with an answer.  

15                    Go ahead, Dr. Beasley. 

16               A.   My belief is, no, if you use the 

17     proper analysis that looked for that sort of 

18     worsening, you will certainly count them.

19               Q.   Now, have you ever heard anybody 

20     before today, before I just kind of expressed that 

21     concern to you, anybody else express a concern to you 

22     that if you're going to go out and try to find this 

23     Teicher and Cole phenomenon, that this might be a 

24     problem, the fact that you might help more than you 

25     hurt?

1               A.   I've heard it expressed that it would 

 2     be difficult to find the phenomenon, in the sense 

 3     that people didn't believe that it existed or it 

 4     substantially occurred much, much, much, much less 

 5     than Dr. Cole and Dr. Teicher's paper suggested at 

 6     3.5 percent; and so it would be impossible to find 

 7     it.

 8               Q.   Did any of the paid consultants that 

 9     Eli Lilly and Company paid in 1990 to advise your 

10     company on this issue and how to go out and test for 

11     this issue tell you exactly what I've just told you 

12     in the hypothetical: that the needle may get buried 

13     in the haystack because you may help more people with 

14     Prozac than you harm?

15               A.   Again, I don't recall the specifics of 

16     the discussion or the things that the consultants 

17     told us.  I have certainly written this down, which 

18     suggests that there was discussion of needle in the 

19     haystack.  Needle in the haystack may well be 

20     referring to the issue of the extreme rarity and, 

21     therefore, the difficulty in studying at all.

22               Q.   Do you know the name Gordon Parker?

23               A.   No, I'm not familiar with that name.

24               MR. VICKERY:  I'm going to ask you to mark 

25     that Beasley Exhibit 2, please.

1                    (The reporter complied.)

 2               MR. VICKERY:  One for you, Mr. See.

 3               MR. SEE:  Thank you.

 4               Q.   BY MR. VICKERY:  For the record, Dr. 

 5     Beasley, we have handed you as Beasley Exhibit 2, 

 6     documents that have PZ control numbers 391 2002 to 

 7     2005.  There is a memorandum to Dr. Weinstein from 

 8     Mr. Haski, dated September 3, 1990; and then there is 

 9     a letter dated August 24th 1990 to Dr. Weinstein, 

10     from Dr. Gordon Parker, professor of psychiatry at 

11     the University of New South Wales.  Have you seen 

12     this document before?

13               A.   I don't recall seeing this document.

14               Q.   Maybe you should take a minute and 

15     have a look at his letter, if you would.  If that 

16     jogs your recollection about seeing it, tell me.  We 

17     don't need to take a lot of time to read that 

18     assignment.

19               A.   Again, it was addressed to Dr. 

20     Weinstein, and I cannot recall specifically seeing this 

21     letter.

22               Q.   Well, you got a letter the same day 

23     from a Dr. Paula Clayton at the University of 

24     Minnesota.  You know Dr. Clayton, don't you?

25               A.   Yes, I do.

1               Q.   You_all are on a first_name basis, 

 2     aren't you?

 3               A.   I know Dr. Clayton only minimally.  I 

 4     would recognize her.  We have never socialized 

 5     together, but I may well have referred to her by her 

 6     first name.

 7               Q.   Let me give you the exchange of 

 8     correspondence between you and Dr. Clayton and see if 

 9     because of the dates if that will help you to put 

10     this other document in context.  

11               MR. VICKERY:  We'll mark these as Exhibit 3 

12     to your deposition.

13                    (The reporter so identified the 

14            document.)

15               MR. VICKERY:  Here's one for you, Mr. See.

16               MR. SEE:  Thank you.

17               Q.   BY MR. VICKERY:  And, again, you don't 

18     need to take all your time to read it, but just 

19     glancing at the correspondence from her to you dated 

20     August 24th, which is PZ 388 815, and your response 

21     of September 5th, which is PZ 388 813 and _14, do you 

22     recall having this exchange of correspondence with 

23     Dr. Clayton on this issue of Prozac and suicide?

24               A.   Obviously, this correspondence 

25     occurred as we have the letters here.  I do not 

1     recall these specific letters prior to you showing 

 2     them to me.

 3               Q.   All right.  I understand it's been ten 

 4     years.  Let's look back at Exhibit 2, if we may, the 

 5     letter from Dr. Parker.   

 6               A.   Okay.

 7               Q.   Sydney, Australia, and look at PZ 391 

 8     2004.

 9               A.   2004.  All right.

10               Q.   The first complete paragraph at the 

11     top there, and I'm going to read.  If you just read 

12     along with me, "Thus," __ I'm starting down kind of 

13     in the middle of the paragraph, or two_thirds down. 

14               MR. SEE:  I'm sorry?

15               Q.   BY MR. VICKERY:  "Thus let us assume."  

16     It's the first complete paragraph about __ 

17               A.   Two_thirds.  

18               Q.   __ two_thirds down.

19               A.   Middle of the line.

20               Q.   "Thus, let us assume," are you with 

21     me?

22               A.   Yes.

23               Q.   "Thus, let us assume base rates of 20%  

24     suicidal ideation in both groups, reducing to 5% in 

25     the FT group" __ that would be fluoxetine therapy; 

1     right?  

 2               A.   Mm_hm.

 3               Q.   That's Prozac, and 15% in the PT, or 

 4     placebo therapy group.

 5               A.   Mm_hm.

 6               Q.   But what if a small percentage, say 1 

 7     percent, of the fluoxetine therapy patients had a 

 8     paradoxical increase in suicidal ideation, the 

 9     overall analysis would show fluoxetine therapy to be 

10     superior to placebo therapy as both a general 

11     antidepressant and in reducing suicidal ideation, and 

12     the paradoxical side effect phenomenon would be 

13     buried.

14                    Isn't that, Doctor, the very same 

15     concern that I asked you about in the hypothetical a 

16     few minutes ago: that by looking for statistical 

17     significance in large groups, you're looking for the 

18     needle in the haystack that you wrote about when you 

19     wrote under Dr. Rosenbaum's comments?

20               MR. SEE:  I object to the form of the 

21     question: that it was asked and it has already been 

22     answered.  

23                    Go ahead, Dr. Beasley.  

24               A.   Again, I have no knowledge of what Dr. 

25     Parker is referring to or when these ana __ 

  1     obviously, the analyses were developed prior to 

 2     September 1990.  I have no knowledge of what those 

 3     specific analyses were.

 4                    If __ if __ one were looking only at 

 5     group improvement in suicidal ideation within a large 

 6     database, a worsening could certainly be obscured.  

 7     That's why it is important to look not only for 

 8     improvement but for increases, substantial increases, 

 9     in suicidal ideation; and, for that matter, for any 

10     worsening, if one were to analyze an available 

11     database.  Those were analyses that were included in 

12     our analysis of the depression database, as well as 

13     the multiple other databases that we looked at, not 

14     just improvement but also worsening.

15               Q.   How about people that dropped out?

16               MR. SEE:  I'm sorry.  I object to the form 

17     of the question.  It's vague __ 

18               MR. VICKERY:  I don't think it's vague.

19               MR. SEE:  __ incapable of being answered.

20               Q.   BY MR. VICKERY:  Do you know what I'm 

21     talking about?  Did you include in your study __

22               A.   Yes.

23               Q.   __ your meta_analysis people that 

24     dropped out?

25               A.   We dropped __ we included all data up 

  1     to the point that patients dropped out.

 2               Q.   But what if they dropped out because 

 3     they were thinking about killing themselves but they 

 4     never told anyone?

 5               MR. SEE:  Object to the form of the 

 6     question.

 7               Q.   BY MR. VICKERY:  If they just dropped 

 8     out, aren't they lost to follow_up, Dr. Beasley?

 9               MR. SEE:  I object to the form of the 

10     question: it's vague.

11               A.   For some patients, it is possible that 

12     we obtain additional data post_discontinuation.  

13     However, you are correct, that once a patient drops 

14     out, we no longer necessarily are collecting 

15     systematic data on that patient.  But we're certainly 

16     endeavoring, as long as the patient is in the 

17     clinical trial, to collect as much data as possible 

18     about that patient.  

19                    People who don't __ and, again, this 

20     is intended to be done by expert psychiatric 

21     interview __ people who are not telling us what they 

22     are experiencing will not be recorded on the case 

23     report form.

24               Q.   You know that 3 to 5 percent of the 

25     patients in the Lilly depression clinical trials 

1     dropped out for psychiatric reasons relating to 

 2     insomnia, and anxiety and restlessness, don't you?

 3               A.   I believe that that number is quite 

 4     correct.

 5               Q.   Now, if those people that were having 

 6     those symptoms __ and that's a trio of symptoms that 

 7     your company frequently referred to as akathisia, 

 8     didn't you?

 9               A.   No, that is a trio that we refer to as 

10     psychomotor activation, I believe.

11               Q.   All right.  And is akathisia another 

12     word which you called psychomotor agitation?

13               A.   Psychomotor activation.  I would 

14     characterize akathisia as one distinct form of 

15     psychomotor activation.

16               Q.   All right.

17               A.   Different from the other forms.

18               Q.   So, roughly, the same percentage of 

19     patients who dropped out of the study for those 

20     reasons, the psychomotor activation, was the same 

21     percentage that Teicher and Cole were projecting as 

22     having this Teicher and Cole phenomenon, wasn't it?  

23     3 to 5 percent?

24               A.   Well, and again, I want to back up 

25     momentarily, because you've said patients dropped 

1     out; they were, in many cases, discontinued by the 

 2     treating physicians and then continued to be treated 

 3     as opposed to what we define as a dropout, meaning 

 4     patients simply leaving and refusing to come back.  

 5     So I think that's an important distinction to make.

 6                    But you're correct, that that 

 7     percentage of patients who Teicher and Cole described 

 8     as possibly having this phenomenon, not related to, 

 9     as I recall, any form of activation, was the 

10     percentage, approximately, that dropped out for these 

11     various adverse events that could be characterized as 

12     psychomotor activation.

13               Q.   So, just mere coincidence?

14               A.   It's my opinion that it is.

15               Q.   All right.  Now, let's move on to 

16     something else.      

17                    What does the word serotonergic mean?

18               A.   I think that's an adjective that would 

19     refer to things connected with serotonin.

20               Q.   Generally speaking, when we talk about 

21     a drug being serotonergic, are we talking about  

22     something that is believed to enhance the 

23     serotonergic activity or function?

24               A.   That wouldn't be my understanding of 

25     the term.  It doesn't have any really precise 

1     meaning.  I would understand that to mean, if you 

 2     used the word, simply a drug that had some influence 

 3     on serotonin.  It could bind to a receptors; it could 

 4     augment transmission; it could inhibit __ 

 5               Q.   Inhibit metabolism?

 6               A.   Inhibit uptake.  I wouldn't 

 7     characterize it as inhibiting metabolism as part of 

 8     that, but that's my thinking.

 9               Q.   All right.  In the spring of '91, your 

10     company submitted a draft study protocol to the FDA 

11     on ways to study this issue, specifically, a 

12     rechallenge study protocol.  Do you recall that?

13               A.   Yes, I was very much involved in the 

14     evolution of that particular potential approach.

15               Q.   Now, how many different Lilly 

16     scientists collaborated in the design and drafting of 

17     that study protocol?

18               Q.   It would be difficult for me to fix on 

19     a specific number.  It was certainly more than ten, 

20     probably less than a hundred.

21               Q.   All right.  Were you the principal 

22     draftsman of the study protocol?

23               A.   I view myself as sort of the 

24     coordinator.  There were certainly areas that I did 

25     not have a particular influence in; there were 

1     obviously areas that I did.

 2               Q.   Now, it was actually submitted to the 

 3     FDA over the signature of Dr. Robert Zerbe.  Do you 

 4     know who Dr. Zerbe is?

 5               A.   Yes, I do.

 6               Q.   And what was his position in the 

 7     company at that time?

 8               A.   I believe at the time he was medical 

 9     director over the entirety of medical development 

10     clinical affairs.

11               Q.   Was he sort of higher up in the 

12     corporate chain than you?

13               A.   Yes.

14               Q.   Considerably?

15               A.   (Nods.)

16               Q.   You wouldn't have come up with this 

17     protocol to submit to the FDA over the signature of a 

18     man as senior of Dr. Zerbe if you thought that it was 

19     flawed in any way, would you?

20               A.   At the time we submitted it, we 

21     certainly would not have viewed it as flawed.  We 

22     would have, since it was draft, certainly considered 

23     it to be a document in evolution.

24               Q.   Sure.  You wanted some feedback from 

25     the FDA on it, didn't you?

1               A.   And potentially others, as well.

 2               Q.   Did you ever circulate that draft to 

 3     any of these private consultants that we've seen in 

 4     the documents or discussed in your testimony today?

 5               A.   I don't recall whether any of these 

 6     specific consultants ever received drafts or not.  

 7     Actually __ excuse me __ one of the names is not 

 8     mentioned in here.  I suppose that I did not take any 

 9     __ any notes on things that he said.  But I believe 

10     that H. John Rush was one of the consultants that had 

11     previously viewed the data.  I believe that Dr. Rush 

12     was an individual who would have been involved in 

13     review of the protocol.

14               Q.   Outside consultant?

15               A.   Outside consultant.  

16               Q.   Is he a man of considerable stature 

17     and reputation in the field of psychopharmacology?  

18     suicidology? psychiatry?  What?

19               A.   I would consider him to be very 

20     prominent in the area of depressive mood disorders.

21               Q.   Where is he?

22               A.   I believe he's at UT Dallas.

23               Q.   How many different outside consultants 

24     did Lilly hire in the 1990_91 time frame to advise 

25     the company with regard to this?

1               A.   I'm uncertain of the specific number.  

 2     I think there were probably something in the order of 

 3     about eight to ten in this country that reviewed 

 4     these data.  There were individuals outside this 

 5     country that reviewed the data for the BMJ and the 

 6     other similar publications, and then there were 

 7     individuals, probably more than 10 and less than 20, 

 8     that reviewed and consulted on the potential 

 9     protocol.

10               Q.   Well, let me ask you this, Dr. 

11     Beasley: We see on Beasley Exhibit 3, the letter to 

12     you from Dr. Paula Clayton, it starts out, "Dear 

13     Charles:  I have read the confidential mail you sent 

14     us on suicidal thoughts and actions for patients who 

15     are given Fluoxetine as compared to placebo or 

16     another tricyclic."  

17                    And then we look over on Beasley 

18     Exhibit 2, and we look at the first paragraph of the 

19     letter from Dr. Parker to Dr. Weinstein, and he says 

20     there on the third line from the bottom, "You have my 

21     assurance that these are expressed in confidence to 

22     your company, respecting the terms of the consultancy 

23     _ even typing this report myself." 

24                    Did your company require people to 

25     keep this so much under wraps that they had to even 

1     type their reports to you themselves?

 2               A.   Not to my knowledge, and I am unaware 

 3     of the specific __ as I said, I didn't __ I don't 

 4     know Dr. Parker nor the nature of the, obviously from 

 5     this, formal relationship that was established for 

 6     the consultation.

 7               Q.   All right.  Back to Dr. H. John Rush 

 8     in Dallas, did you have any working relationship with 

 9     him before your rechallenge protocol was submitted to 

10     him?

11               A.   I had known Dr. Rush __ I'm trying to 

12     recall if he was ever an investigator on a study that 

13     I had some responsibility for.

14                    He was an investigator on a study of 

15     another antidepressant that Lilly was developing, and 

16     that was the context in which I came to know Dr. 

17     Rush.  

18               Q.   Was it your idea or somebody else's 

19     idea in the company that you run the rechallenge 

20     study protocol by Dr. Rush before it was submitted to 

21     the FDA?

22               A.   Well, we in fact had a group of __ 

23     well, first of all, my recollection is that it was 

24     submitted to the FDA fairly early on in the process 

25     of thinking about it, and it was actually fairly 

1     later in the process that we had consultants review 

 2     the draft protocol.

 3               Q.   All right. 

12               Q.   Dr. Beasley, before the break, we were 

13     talking about the rechallenge protocol that you 

14     drafted and that was submitted to the FDA in March of 

15     1991.  In addition to being the principal draftsman 

16     of the document, you were also going to be the 

17     medical director to sort of supervise that study if 

18     it had been done, weren't you?

19               A.   That would have possibly been the case 

20     at that point in time.  Again, given my sort of 

21     shifting to olanzapine in_the_future from the 

22     not_too_distant_future, it would have been unclear as 

23     to whether or not I would have continued to be 

24     involved in that.

25               Q.   At the time of your deposition in May 

1     of '94, you testified that that study had not been 

 2     done and that you did not know why.  Is that still 

 3     the situation today?

 4               A.   I am not precisely aware of the 

 5     reasons that that study was not conducted.  There 

 6     were certainly alternative methodologies that were __ 

 7     and that Lilly just continued to use to evaluate this 

 8     issue of suicidality.  This study was not one of 

 9     those specific ways that this was approached.

10               Q.   Has the company ever done this study 

11     or anything like it?

12               A.   The company has not done this specific 

13     study.  When we met with our consultants to consider 

14     the conduct of this particular protocol, there were a 

15     number that, although indicating that they would be 

16     willing to try it, raised some rather significant 

17     reservations about the specific doability of this 

18     particular protocol.

19               Q.   Look, if you would, on Exhibit 1, the 

20     handwritten notes __

24               Q.   Do you see where the PZ numbers are, 

25     391?  It's about the third page over, 2022.  

1               A.   That's the page I have here.  

 2               Q.   Okay.  Do you see there, near the 

 3     bottom, about five lines up from the bottom, under 

 4     "Rosenbaum,"  you put, "If exists won't find _ don't 

 5     look at means _ find then rechallenge."  Was that 

 6     comment by Dr. Rosenbaum the thing that got you 

 7     thinking along the lines of designing a rechallenge 

 8     study protocol?

 9               A.   Well, actually, I think we had been 

10     considering this as one of the options in terms of 

11     methodology prior to this particular __ prior to this 

12     particular meeting.  This had been something that we 

13     had given consideration to internally.  Now, the 

14     timing of this, I'm uncertain about, but my best 

15     recollection is, that this was one of the things that 

16     was considered by Lilly prior to any outside 

17     consultant. 

18               Q.   Does any one person within Lilly get 

19     credit or blame, whichever is appropriate, for coming 

20     up with the notion of using rechallenge as a means to 

21     test this notion that this drug could cause some 

22     people to become violent or suicidal?

23               A.   I'm not sure specifically any one 

24     person would get the credit or blame for this.  

25     Again, a lot of things were being thought about in 

1     the ways to address this issue prior to this point in 

 2     time.

 3               Q.   Well, you've told me a few minutes ago 

 4     that somewhere between ten and a hundred people were 

 5     involved in the drafting of the protocol, rechallenge 

 6     protocol.

 7               A.   That's correct.

 8               Q.   Did any of those people come forward 

 9     and say, "Wait.  Stop.  This is not a scientifically 

10     valid way to test the hypothesis that Prozac causes 

11     some people to become suicidal?" 

12               A.   My recollection is that, as we moved 

13     past the advisory committee on the specific protocol, 

14     there were increasing reservations expressed by some 

15     individuals on the doability and, in fact, the 

16     adequacy of the instrumentation; and the protocol was 

17     specifically to address Dr. Teicher's phenomenon as 

18     it was initially designed.  

19               Q.   Okay.  Maybe I didn't ask my question 

20     clear enough.  Let me try it again.  

21                    Prior to the time it was submitted to 

22     the FDA, when somewhere between ten to a hundred 

23     Lilly people were working on it, did anybody say, 

24     "Wait.  Don't write the study protocol.  Don't submit 

25     it to the FDA.  This is not a scientifically valid 

1     way to study this issue"?

 2               A.   Not prior to the submission to the 

 3     submission to the FDA.  

 4               Q.   All right.  Now, when your article was 

 5     published in the BMJ, the meta_analysis article, that 

 6     was kind of a big feather in where your cap, wasn't 

 7     it?

 8               A.   It is the only publication that I've 

 9     had in the British Medical Journal, which is a 

10     prestigious journal.

11               Q.   All right.  And Dr. Healy and, I 

12     believe, Dr. Crane had written a letter to the editor 

13     raising some concerns about your article and had 

14     suggested rechallenge as a way to look into this 

15     issue, hadn't they?

16               A.   I recall an exchange of letters to the 

17     editors.  I don't recall the specifics of Dr. Healy 

18     and Crane's letter to the editor.

19               Q.   Do you recall that when you wrote back 

20     in response to their letter that you said, 

21     "Rechallenge is a scientifically appropriate way to 

22     look into this issue"?

23               A.   I'm sure it's a scientifically 

24     appropriate way.  The practicalities of implementing 

25     this study __ and, for that matter, potentially the 

1     ethics __ might well be, on the one hand, extremely 

 2     difficult and, on the other hand, potentially 

 3     questionable.

 4               Q.   All right.  Back to Dr. Rush for just 

 5     one minute here, because I see I have a note here to 

 6     ask you: Did you ever meet with him in person or talk 

 7     to him over the phone about the rechallenge protocol?

 8               A.   As I recall, he was one of the 

 9     consultants who reviewed the particular __ this __ 

10     well, I don't know, again, if it was the one that you 

11     make reference to that we submitted to the Food and 

12     Drug Administration in March.  It could have 

13     certainly evolved prior to discussion with 

14     consultants.  But, yes, I did have a personal meeting 

15     with consultants on the protocol.

16               Q.   In Indianapolis or down in Dallas?

17               A.   In Indianapolis.  

18               Q.   So Dr. Rush flew up from Dallas and 

19     met with you and others here to discuss it?

20               A.   That's correct.  

21               Q.   Were there other outside consultants 

22     at that meeting?

23               A.   Yes, we had a group.

24               Q.   Who else was in that group?

25               A.   I don't recall the entirety of the 

1     group.  Dr. Ivan Miller was one individual that I can 

 2     recall.  The other specific individuals I don't 

 3     recall.  

 4               Q.   Where is Dr. Ivan Miller?

 5               A.   He is in Rhode Island.

 6               Q.   Do you know who Dr. J. John Mann is?

 7               A.   Yes, I do.

 8               Q.   Who is he?

 9               A.   He is a __ actually, I believe now he 

10     is at Columbia.  He is a full professor of 

11     psychiatry, has had a longstanding interest in 

12     suicide, specifically as a psychiatrist, was 

13     previously a full professor at the University of 

14     Pittsburgh, and I believe now he's full professor at 

15     Columbia University.

16               Q.   And he's also a 

17     neuropsychopharmacologist, isn't he?

18               A.   That's correct.

19               Q.   Do you know that he is the author of 

20     the ACNP Consensus Statement that was issued in March 

21     of 1992 on this issue of Prozac and suicide?

22               A.   Yes, I am. 

23               Q.   And are you aware of the fact that he 

24     and his colleague, Dr. Kapur, published an article in 

25     1991 on this issue?

1               A.   Yes, I am.

 2               Q.   I have heard others refer to Dr. Mann 

 3     as probably the preeminent suicidologist in this 

 4     country, if not the world.  Is that your 

 5     understanding of his stature?

 6               A.   I'm not sure I would say he was "the"; 

 7     I would say he is extremely prominent in this area.

 8               Q.   Was he ever hired by Lilly as an 

 9     outside consultant on this issue?

10               A.   We had conversations with him about 

11     these issues.  I do not know whether he was formally 

12     paid as an outside consultant or not.

13               Q.   All right.  So he was working with 

14     you, whether he was getting paid or not?

15               A.   Oh, to some extent.

16               MR. VICKERY:  All right.  Let's mark this 

17     as Beasley Exhibit 4, if we may.  

1               A.   August 17th 1990. 

 2               Q.   Do you recall getting that letter?

 3               A.   Not specifically receiving this 

 4     letter, no.

 5               MR. VICKERY:  Well, Mr. See, did I give you 

 6     my copy?

 7               MR. SEE:  You gave me a copy.  

 8               MR. VICKERY:  Well.

 9               MR. SEE:  It doesn't have any notes or 

10     marks on it.

11               MR. VICKERY:  Unless I've __ I had an extra 

12     copy, but evidently __ I don't know what I've done 

13     with it.  Ah, there it is.  Okay.

14               Q.   He says here, "As you know we have 

15     been amongst the major proponents of the Serotonin 

16     Hypothesis of suicidal behavior and aggression."  Do 

17     you know what he's talking about, the Serotonin 

18     Hypothesis?

19               A.   Again, this would relate back to my 

20     understanding that the hypothesis is that there's a 

21     decrease in serotonergic function that influences and 

22     increases the possibility of either suicidal behavior 

23     or externally aggressive behavior.  

24               Q.   All right.  Turn to page 2 of that 

25     letter, if you would, and I just want to focus your 

1     attention on one sentence in the middle of that 

 2     paragraph.  "Since, the drug reaches steady state 

 3     levels in about four to six weeks, symptomatology 

 4     that develops well after that time is more likely to 

 5     be related to the condition for which the drug is 

 6     being administered rather than to the drug."  Do you 

 7     agree with him?

 8               A.   I would consider this to be a 

 9     hypothesis.  I have no sound basis for making this as 

10     an assumption.  My general position would be that the 

11     longer an individual is on a medication, the less 

12     likely any shift or change in that particular 

13     individual is due to the medication as a general 

14     hypothesis.  But, as a scientist, I don't have 

15     empirical validation.

16               Q.   I understand.  And is the converse 

17     true?

18               A.   I'm not sure that I would view the 

19     converse as a hypothesis that I would likely 

20     personally entertain or believe in.  My focus has 

21     been on thinking about, again, very, very late 

22     effects after one starts a particular medication as 

23     being unlikely related drug.  I think as one starts a 

24     medication, where disease is still present, there are 

25     a number of compounds with regard to what any 

1     particular event or happening might be.

 2               Q.   But if we are concerned about the 

 3     possibility that the drug is causing this horrible 

 4     behavior __ and we're specifically talking about the 

 5     Teicher and Cole phenomenon here __ the fact that the 

 6     behavior or the thinking occurred shortly after the 

 7     drug is initiated or a dose is increased, is one of 

 8     the factors that tends to suggest the drug may be 

 9     causing it, isn't it?

10               A.   I don't __ again, I don't necessarily 

11     agree with that position.  You've referred to Dr. 

12     Teicher and Dr. Cole's paper.  And, again, I think 

13     they had a fairly wide period, in terms of weeks __ 

14     we're not talking months or years __ in which they 

15     described these cases.

16                    So, from my perspective, it's unlikely 

17     that a late_onset event is related.  As one gets 

18     closer to drug initiation, that statement becomes 

19     less believable by me.  But I would not accept the 

20     statement that if it happens early, it is necessarily 

21     more likely to be drug related or not. 

22               Q.   I wasn't suggesting that it was.  I 

23     was suggesting that that's one of the factors that, 

24     when you're trying to say, "Is it drug related?" 

25     that's one of the factors you look to: Did it happen 

1     right after the drug came?  Is that one of the 

 2     factors you look to or not? 

 3               MR. SEE:  I object to the question as it's 

 4     the same question that was asked and just answered. 

 5                    Go ahead, Dr. Beasley.

 6               A.   Again, I would tend to discount an 

 7     event that happened a long time out.  I would give, 

 8     perhaps, some consideration to temporal proximity, 

 9     meaning an event that occurred shortly after 

10     initiation of a drug, but not very much, personally.

11               Q.   BY MR. VICKERY:  What else would you 

12     look to?  What other factors would you look at to try 

13     to decide, is the drug causing this, or not?

14               A.   I would want very, very detailed 

15     information on the individual patient, but then I 

16     would also look to the profile of the drug.  And 

17     that's my primary basis for assessment of a 

18     causality.  Do we have data that supports that this 

19     particular phenomena does occur in patients at an 

20     increased rate relative to nontreatment or an 

21     alternative treatment?

22               Q.   Would you look to see __ are you 

23     saying, when you say the profile of the drug, would 

24     you look to see if there is some biologically 

25     plausible explanation for just how and why it is that 

 1     this drug would be causing this behavior?

 2               A.   That's not my __ that's not what I 

 3     meant by "profile."  What I was talking about with 

 4     profile is those events or phenomena that are 

 5     established as occurring with substantially more 

 6     frequency with your test substance than with placebo 

 7     or an alternative substance.

 8                    My concern with a biological 

 9     hypothesis is that there are many, many biological 

10     hypotheses to potentially explain a phenomenon in 

11     terms of relation to another biological factor that 

12     are just that, that are just hypotheses, and I don't 

13     like to see those begin to carry, in my way of 

14     thinking about things, the weight of proof.

15               Q.   Other than lowered levels of 5HIAA in 

16     the mindstones of people who kill themselves, can you 

17     tell me any other biological marker of suicide?

18               A.   I believe there are __ and I believe 

19     Dr. Mann is one of the individuals who has seen 

20     differences in serotonin receptors, but I can't 

21     recall the specifics of that research.

22               Q.   Okay.  But your focus would be on 

23     whether there is proof of an association to a 

24     statistically significant degree; is that what you're 

25     telling me?

 1               A.   That's correct.

 2               Q.   And if that is your focus, Dr. 

 3     Beasley, don't you miss the needle in haystack?

 4               A.   Not necessarily.  I mean, again, it 

 5     depends upon the nature of the study, the database 

 6     that one has to look at.  And there have been 

 7     multiple, multiple databases that have been evaluated 

 8     with respect to this issue.

 9               Q.   You were questioned at some length in 

10     your prior deposition about the meta_analysis itself, 

11     and I don't see any need to rehash that issue with 

12     you here.

13                    Do you remember if a label change was 

14     made on the Prozac label in the spring of 1990, sort 

15     of in the wake of and in response to this Teicher and 

16     Cole paper?

17               A.   Yes, a label change was made. 

18               Q.   What was the label change?

19               A.   It was to add "suicidal ideation" and, 

20     I believe, the other term was "violence," or it may 

21     have been "aggression."  I'm not sure which term was 

22     added.

23               Q.   To add them where?

24               A.   To add them in the postintroductory 

25     report section of the label.

 1               Q.   Now, is that section of the label 

 2     preceded by a causal disclaimer?

 3               A.   I believe that the __ yes, it is.

 4               Q.   By causal disclaimer, we mean that the 

 5     label says, "There are some things that have been 

 6     reported, but we're not saying our drug causes them, 

 7     and here they are," and then lists them.  Isn't that 

 8     __

 9               MR. SEE:  I object to the form of the 

10     question.  The label as it is written speaks for 

11     itself.

12               MR. VICKERY:  Let me rephrase my question.

13               Q.   What do you mean by "causal 

14     disclaimer"? 

15               A.   What I mean by "causal disclaimer" is 

16     that it is stated that these things have been 

17     observed in temporal relationship, but that does that 

18     not prove or demonstrate causality.  My sense is that 

19     it leaves the question, from a regulatory perspective 

20     and a clinical perspective, in the air as it's 

21     stated.

17               Q.   Did you go to the September 1991 PDAC 

18     meeting?

19               A.   No, I did not.

20               Q.   How many suicides have there been that 

21     have been reported in temporal proximity of people 

22     starting on Prozac?

23               A.   I do not know the specific number of 

24     __ and I believe you said completed suicides __ 

25               Q.   Right.

 1               A.   __ that have been reported in terms of 

 2     association with Prozac.  I think your question asks 

 3     about starting or initiation, and I certainly don't 

 4     know that.  I'm not sure how we would define that.  

 5     But neither number am I aware of.

 6               Q.   The number of suicides reported in 

 7     temporal association with Prozac is in the hundreds, 

 8     isn't it, if not thousands?

 9               MR. SEE:  I object to the question.  The 

10     witness has just answered your question.

11               A.   I do not know the number; and, again, 

12     you're talking about orders of magnitude that I'm 

13     uncertain about that, so I cannot hazard a 

14     speculation.  

15               Q.   BY MR. VICKERY:  All right.  I think 

16     you were asked about that in May of '94, and you were 

17     certainly closer to it at that time, weren't you?

18               A.   Yes.

19               Q.   Dr. Beasley, of those that are 

20     reported, what is your company's view on what 

21     percentage of the adverse effects that are comprised 

22     by that?  Do you know what I mean?

23               MR. SEE:  I object to the question: it's 

24     vague. 

25               MR. VICKERY:  Yeah, it's really bad.  

 1     That's a very good objection.  Let me see if I can do 

 2     better.

 3               Q.   What percentage of adverse effects 

 4     does your company believe actually get reported?

 5               A.   There are actually some literature on 

 6     this, and the literature suggests that it is between 

 7     one in five and one in thirty, with the more serious 

 8     events, particularly fatalities, being closer to the 

 9     one in five.

10               Q.   So, if there are five deaths reported 

11     __ if there are five deaths reported, then you 

12     believe that there are really 25 out there?

13               A.   There, as I said, there are literature 

14     to suggest that.  It's also complicated in terms of 

15     __ and there are publications on this __ with regard 

16     to where the drug is in its life cycle; shifts over 

17     time, regardless of where a drug is.  In other words, 

18     early on, there are more reports than later on, and 

19     over time with drugs, there is likely to be more 

20     reporting of adverse events.

21               Q.   All right.  Have you ever testified in 

22     a lawsuit other than the last deposition and this 

23     one?

24               A.   No, I haven't.  

25               Q.   Have you ever been assigned by your 

 1     company to help out a prosecutor that was trying to 

 2     prosecute somebody for a crime where they were faced 

 3     with a Prozac defense?

 4               A.   I've certainly had some contact with 

 5     prosecutors.  I can recall one __ I can recall one 

 6     case.  It was not a Prozac defense case; it was a 

 7     case where there was __ it's a strange and difficult 

 8     case, but __

 9               Q.   If it's not relevant, let's don't take 

10     our time with it.  If it doesn't have anything to do 

11     with Prozac __

12               A.   It had to do with Prozac, and it had 

13     to do with whether a __ and I forget whether it was a 

14     husband or wife murdered their spouse by 

15     surreptitiously and secretly administering them 

16     Prozac in their coffee.

17               Q.   Okay.  Sort of an Arsenic and Old Lace 

18     version.  All right.  I'm very close.  Let me just 

24               Q.   BY MR. VICKERY:  Dr. Beasley, has your 

25     company ever attempted to plot or graph reports of 

 1     suicidal ideation and acts of completed suicides as a 

 2     function of Prozac prescriptions?

 3               A.   I am uncertain as to whether we have 

 4     ever done this or not.  I don't recall visually 

 5     seeing this done.

 6               Q.   I think that the court reporter has 

 7     marked here as Exhibit 5 a graph which I believe to 

 8     be that.  I may be misspeaking.  Do you recognize 

 9     this?

10               A.   I don't recall seeing this 

11     specifically previously.  It would appear to be, to 

12     me, a __ as you described __ a graph looking at 

13     suicidal ideation, nonfatal suicidal acts, and fatal 

14     suicide acts by quarter of time.

15               Q.   Dr. Beasley, when you_all analyzed 

16     this question of Prozac and suicide, did you analyze 

17     it in terms of patient days?

18               A.   Again, I do not recall the __

19               Q.   I don't think you're going to find it 

20     on that document there.

21               A.   No, I'm not going to find it here.  

22     And I don't recall whether or not the __ and this is 

23     analysis of the adverse reporting data, I feel fairly 

24     certain __ whether that was ever done in terms of 

25     average days or total days of therapy, or simply the 

 1     number of patients, the former being called "rate," 

 2     and with the patients being called "incidents."

 3               Q.   Well, you used patient days as the 

 4     mode of analysis, either in the meta_analysis or in 

 5     the analysis that you submitted to the FDA in 1990 on 

 6     this issue, didn't you?  

 7               A.   I don't recall __ and, again, I would 

 8     recall much better the BMJ than the total FDA 

 9     submission __ my recollection is that that was 

10     incidence data as opposed to rate data, so that that 

11     was not done in terms of patient days.

12               Q.   Is the use of patient days a fair way 

13     to analyze this issue?

14               MR. SEE:  Objection to the question: it's 

15     vague.  "This issue" is not defined.

16               MR. VICKERY:  The issue of whether or not 

17     Prozac causes some patients to become violent or 

18     suicidal.

19               Q.   Is the use of patient days, as a means 

20     of analysis, a fair thing to do?

21               A.   Patient days __ analysis based on 

22     patient days could be very useful to you, depending 

23     upon the specific analysis that you were doing.

24               Q.   Well, let me ask you this.  I mean, if 

25     you're counting on patient days, and three patients 

 1     each take it, and they take it for a year without 

 2     incident, that's 3 times 365 patient days where 

 3     everything is okay; isn't it?

 4               A.   That's correct.

 5               Q.   And if patient No. 4 takes it four a 

 6     week and blows their brains out, that's only 7 

 7     patient days before this adverse effect, isn't it?

 8               A.   That's correct.

 9               Q.   And if we lump them all together and 

10     analyze them in terms of patient days, we have over a 

11     thousand days split among four patients, don't we?

12               A.   That's correct.  

13               Q.   And isn't that misleading?

14               A.   I would not view that as misleading, 

15     if analyzed in an appropriate imperative fashion.  

16     Suicide is something __ suicidal ideation, again, as 

17     we've said, is something that happens oftentimes 

18     very, very abruptly.  It can happen when people are 

19     young; it can happen when people are old; it can 

20     happen early in therapy; it can happen late in 

21     therapy; it can happen outside the context of 

22     therapy.  

23                    And when you're trying to analyze an 

24     event like this, the total time that you have in 

25     terms of exposure, of comparative exposure, is from 

 1     my perspective very important.

 2               Q.   But isn't it important if the 

 3     phenomenon you're looking for is one that manifests 

 4     itself early in the drug therapy, isn't it important 

 5     to look at that in a discrete and separate way? 

 6               MR. SEE:  I object to the question as an 

 7     improper hypothetical.

 8               A.   Again, depending upon what you're 

 9     looking at, it would be very, very appropriate to 

10     look at total patient days, as I've said.  That tends 

11     to be something that we do outside of this partic __ 

12     and, again, I don't recall whether this issue was 

13     analyzed in those terms, or not, but we certainly 

14     apply this form of analysis with other phenomena with 

15     other drugs that I've been associated with.  It's 

16     been well accepted by regulatory bodies, scientists.

17                    Now, you could certainly put forward a 

18     hypothesis in which you were interested in events 

19     occurring early, very specifically, and you could 

20     truncate your analysis within that particular time 

21     frame.  Then it becomes more like an incidence 

22     analysis.

23               Q.   BY MR. VICKERY:  Has your company ever 

24     done that with respect to the Teicher phenomenon?

25               A.   Well, again, from my perspective, 

 1     because what we did in the BMJ article was an 

 2     incidence analysis.  Regardless of when it occurred, 

 3     you got counted as a case.  If it occurred at one 

 4     day, we picked that up.  That was independent of a 

 5     time_to_event analysis.

 6               Q.   But there, again, if the patient 

 7     merely dropped out because of the psychiatric reasons 

 8     without telling the doctor that he or she was 

 9     developing this intense suicidal ideation, then that 

10     patient would be lost to follow_up, wouldn't they?

11               A.   Well __ and, again, there are __ the 

12     number of patients that were actually dropped out, as 

13     opposed to discontinued by their physician, I believe 

14     is quite small __ very, very small.

15               Q.   Nonetheless, if either the patient 

16     doesn't tell or the doctor doesn't ask, if a patient 

17     is discontinued, whether they drop out or the doctor 

18     drops them out, if no one thinks to ask about 

19     suicide, that patient can be lost to follow_up for 

20     purpose of that epidemiological analysis, can't they, 

21     sir? 

22               MR. SEE:  I object to the form of the 

23     question as an improper hypothetical, and it calls 

24     for speculation.

25               A.   If patients don't tell, physicians 

 1     don't ask, then you're not going to know.

 2                    Our protocol mandated that physicians 

 3     inquire, interview, at a discharge visit.  As long as 

 4     they were seeing the patients, they were to do 

 5     psychiatric evaluation.

 6               Q.   BY MR. VICKERY:  Okay.  We've already 

 7     discussed the fact that in January of 1990 you flew 

 8     to Boston to meet with Dr. Teicher and Dr. Cole; 

 9     right?

10               A.   That's correct.

11               Q.   Have you done other travel outside of 

12     the state of Indiana with respect to this issue of 

13     Prozac and suicide?

14               A.   I'm trying to recall my travels.  I've 

15     traveled a lot in the last nine years on a variety of 

16     topics.

17               Q.   Let me just short circuit, then, and 

18     ask you: Has your company asked you to travel out of 

19     state from time to time on company business?

20               A.   Yes.

21               Q.   And when they ask you to do it, do you 

22     do so?

23               A.   Yes.

24               Q.   So that if, for example, we were going 

25     to have a trial of a lawsuit somewhere in the United 

 1     States, and your company said, "Dr. Beasley, we want 

 2     you there; we want the jury to see you and hear you; 

 3     we want you to travel there"; you would do what they 

 4     asked you to, wouldn't you?

 5               A.   I mean, I suppose the possibility 

 6     exists where I wouldn't, but I can't think of many 

 7     possibilities. 

 8               MR. VICKERY:  All right, sir.  In view of 

 9     that, I'm not going to go ask you any more questions 

10     today.

14               QUESTIONS BY MR. SEE

15               Q.   Dr. Beasley, two things to clarify.  

16     Would you just remind us: When did you last have 

17     significant responsibilities regarding Prozac as part 

18     of your duties at Lilly?

19               A.   I moved off of Prozac as an assigned 

20     responsibility, I believe it was either October or 

21     November of 1991.

22               Q.   And Mr. Vickery asked you some 

23     questions, and he made reference to 3 to 5 percent of 

24     patients dropping out of Prozac clinical trials 

25     because of anxiety, nervousness, and/or insomnia.  Do 

 1     you recall that?

 2               A.   Yes, and __

 3               Q.   I mean, do you recall him asking you 

 4     that?

 5               A.   Yes, and I misstated.  To me, drop out 

 6     means __ should mean __ a very technically precise 

 7     thing, of people leaving abruptly without, 

 8     essentially, notifying their psychiatrist of the 

 9     reason.  The clarification is that patients were 

10     discontinued at approximately 3 to 5 percent.

11               Q.   And what you're saying is that a 

12     proportion of these patients continued to see their 

13     doctors; they just weren't in the study anymore?

14               A.   That would be true.

15               Q.   Now, this is the question: Is there 

16     any evidence that you and Lilly discovered, Dr. 

17     Beasley, that these 3 to 5 percent of patients 

18     discontinued from Prozac studies that Mr. Vickery was 

19     referring to, that these patients had the condition 

20     akathisia?

21               A.   No, that has been a condition very 

22     rarely reported in the clinical trials.

23     REDIRECT EXAMINATION

24               QUESTIONS BY MR. VICKERY

25               Q.   Did you look for it?

 1               MR. SEE:  I object to the question as being 

 2     vague. 

 3               Q.   BY MR. VICKERY:  Akathisia.  Did you 

 4     look for the akathisia in those patients that dropped 

 5     out?

 6               A.   We looked for all adverse events in 

 7     all patients who were discontinued.  

 8               Q.   Did you specifically go back and look 

 9     for akathisia?

10               A.   In retrospect, yes, we looked and we 

11     evaluated the reasons for discontinuation and the 

12     adverse events of those patients that were recorded 

13     at the time of discontinuation.

14               Q.   Did you interview the doctors or the 

15     patients to find out whether or not they were 

16     akathisic?

17               A.   No, we did not.  It was the 

18     responsibility of the physicians to appropriately 

19     evaluate for adverse events and record those. 

20               Q.   Did you use the Barnes scale for 

21     measuring treatment emergent akathisia?

22               A.   We did not use the Barnes scale in 

23     older studies, which is a scale that's intended to 

24     rate severity of akathisia once diagnosed.

25               Q.   Did you use any kind of treatment 

 1     instrument in the clinical trials to detect or 

 2     measure the severity of treatment emergent akathisia?

 3               A.   Well, again, with this being a rare 

 4     event, we did not have it available for assessment 

 5     and measurement except rarely.  In specific answer to 

 6     your question, no, we did not use a specific scale 

 7     for measurement of severity.  Physicians, I should 

 8     say, are required to rate severity of adverse events 

 9     on a three_point scale of being mild, moderate, and 

10     severe. 

11               Q.   After Dr. Tollefson made the comment 

12     which caused you to write on the handwritten note, 

13     Beasley Exhibit 1, "Risk is related to akathisia," 

14     after that, did your company do anything about it?

15               A.   Yes, we did.  There was conducted an 

16     analysis that looked very specifically, not just at 

17     akathisia as an event, but this clustering of events 

18     that have a component of psychomotor activation with 

19     them, along with a number of other psychiatric or 

20     behavioral states, and we did not find the 

21     relationship, first of all, between these events and 

22     suicide in patients taking Prozac.

23               Q.   Dr. John Mann has told me in a 

24     deposition that he considers akathisia to be a risk 

25     factor for suicide.  Has he ever told you or anyone 

 1     else at Lilly that, to your knowledge?

 2               A.   I __

 3               MR. SEE:  Hold on, Dr. Beasley.  I object 

 4     to the testifying by counsel and move that it be 

 5     stricken.  I won't object if you just ask a question.

 6               Q.   BY MR. VICKERY:  Has Dr. Mann ever 

 7     told you or anyone else at Lilly, to your knowledge, 

 8     whether akathisia is a risk for suicide? 

 9               A.   I don't recall specifically being told 

10     that by Mr. Mann.

11               Q.   Do you think that akathisia is a risk 

12     for suicide?

13               A.   Based on the data that we have 

14     reviewed, I do not believe that it is.

19     RECROSS_EXAMINATION

20               QUESTIONS BY MR. SEE

21               Q.   Dr. Beasley, is akathisia a condition 

22     that is diagnosed by using a scale like the Barnes 

23     scale?

24               A.   Akathisia is a clinical condition 

25     that, to my understanding, has two components that 

 1     are diagnosed clinically.  It has a subjective 

 2     component and an objective component.

 3               MR. SEE:  Thank you, sir.
6               QUESTIONS BY MR. VICKERY

 7               Q.   Have you ever read the Sepracor patent 

 8     __

 9               A.   No, I haven't.

10               Q.   __ on R(_)fluoxetine? 

11               A.   No.

12               Q.   Do you know what that is?

13               A.   R(_)fluoxetine?  Yes.  

14               Q.   You know what R(_)fluoxetine is, don't 

15     you?

16               A.   Yes, it's one of the enantiogeneric 

17     isomers of the racemate of fluoxetine.  

18               Q.   Do you have any reason to believe from 

19     a pharmacological standpoint that the single isomer 

20     version of fluoxetine hydrochloride would be less 

21     likely to cause any side effects than the racemic 

22     mixture?

23               A.   I believe it has some differences in 

24     its binding profile.  That's my knowledge of it, in 

25     terms of its binding to a number of receptors besides 

1     the primary function being to inhibit serotonin 

 2     uptake.  

 3                    Whether or not that is clinically 

 4     relevant to anything, I don't know; but I know that 

 5     it has some differences in binding characteristics. 

 6               MR. VICKERY:  Okay.   No further questions.

 7               MR. SEE:  Thank you, Dr. Beasley.