1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

              PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE

 

                    WITH THE PEDIATRIC SUBCOMMITTEE

 

             OF THE ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

 

 

 

 

 

                        Monday, February 2, 2004

 

                               8:00 a.m.

 

 

 

                          Holiday Inn Bethesda

                          Versailles I and II

                         8120 Wisconsin Avenue

                           Bethesda, Maryland

 

                                                                 2

 

                              PARTICIPANTS

 

      Matthew Rudorfer, M.D., Chair

      Anuja M. Patel, M.P.H., Executive Secretary

 

      PSYCHOPHARMACOLOGICAL DRUGS ADVISORY COMMITTEE

           MEMBERS

                Tana Grady-Weliky, M.D.

                Irene E. Ortiz, M.D.

                Richard P. Malone, M.D

                Wayne K. Goodman, M.D.

                James J. McGough, M.D.

                Jean E. Bronstein, R.N., M.S.

                  (Consumer Rep)

                Andrew C. Leon, Ph.D.

                Philip S. Wang, M.D. M.P.H., Dr. P.H.

                Dilip J. Mehta, M.D., Ph.D.,

                  (Industry Rep)

 

      ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

           MEMBERS

 

                Steven C. Ebert, Pharm. D. (Consumer Rep)

                Mary P. Glode, M.D.

                Samuel D. Maldonado, M.D., M.P.H.

                  (Industry Rep)

 

      PEDIATRIC SUBCOMMITTEE OF THE ANTI-INFECTIVE DRUGS

      ADVISORY COMMITTEE MEMBERS

 

                P. Joan Chesney, M.D.

                Mary Glode, M.D.

                Steven Ebert, Pharm. D. (Consumer Rep)

                Robert Nelson, M.D., Ph.D.

                Richard Gorman, M.D., FAAP

                Robert J. Fink, M.D.

                Susan Fuchs, M.D.

                David Danford, M.D.

                Victor Santana, M.D.

                Mark Hudak, M.D.

                Judith R. O'Fallon, Ph.D.

 

      SGE CONSULTANTS (VOTING)

 

                Elizabeth B. Andrews, Ph.D.

                Norman Fost, M.D., M.P.H.

                Charles E. Irwin, Jr., M.D.

                Lauren K. Leslie, M.D., FAAP

                James M. Perrin, M.D.

                Cynthia R. Pfeffer, M.D.

 

      SGE PATIENT REPRESENTATIVE (VOTING)

 

                Gail W. Griffith

 

                                                                 3

 

                        PARTICIPANTS (Continued)

 

      GOVERNMENT EMPLOYEE (non-voting)

 

                Daniel S. Pine, M.D.

 

      FDA

 

                Robert Temple, M.D.

                Russell G. Katz, M.D.

                Thomas Laughren, M.D.

                M. Dianne Murphy, M.D.

                Susan Cummins, M.D., MPH

                Anne Trontell, M.D., MPH

 

                                                                 4

 

                            C O N T E N T S

                                                              PAGE

      Call to Order and Opening Remarks:

                Matthew Rudorfer, M.D.                           6

 

      Introductions                                              8

 

      Conflict of Interest Statement:

                Anuja M. Patel, MPH                             15

 

      Overview of Issues:

                Russell Katz, M.D.                              19

 

      Pediatric Drug Development Program:

                Dianne Murphy, M.D.                             26

 

      Pediatric Depression and Its Treatment:

                Cynthia R. Pfeffer, M.D.                        39

 

      Suicide and Related Problems in Adolescents:

                David Shaffer, FRCP (Lond) FRC Psych            60

 

      Open Public Hearing

                Irving Kirsch and David Antonuccio              79

                Lisa Van Syckel                                 82

                Ann Blake Tracy, Ph.D.                          83

                Tom Woodward                                    85

                Mark Miller                                     87

                Corey and Jay Baadsgaard                        90

                Joyce Storey                                    91

                Jame Tierney                                    93

                Donna and Mark Taylor                           95

                Shannon Baker                                   97

                Dawn Rider                                      98

                Sara Bostock                                   100

                Vera Hassner Sharav                            103

                Cynthia Brockman                               104

                Todd and Eileen Shivak                         107

                Andy Vickery                                   109

                Rosie Carr Meysenburg                          111

                Rachel Adler                                   112

                Pepper Draper                                  115

                Donald Marks, M.D., Ph.D.                      117

                Leah Harris                                    119

                Donald Farber                                  121

                Lorraine Slater                                123

                Matthew Piepenberg                             125

                Terri Williams                                 127

                Glenn McIntosh                                 129

                Delnora Duprey                                 132

                Joe Pittman                                    133

                Richard Mack                                   135

                Noah Wright Smith                              137

                Marion Goff                                    139

 

                                                                 5

 

                      C O N T E N T S (Continued)

 

                                                              PAGE

      Open Public Hearing (Continued)

                Gary Cheslek, M.D.                             142

                Sherri Walton                                  144

                Peter R. Breggin, M.D.                         146

                Robert Fritz                                   148

                Lawrence Greenhill, M.D.                       151

                Suzanne Vogel-Scibilia, M.D.                   152

                Dennis Winter                                  155

                Steve Cole                                     157

                Allan Routhier                                 158

                Daniel J. Safer, M.D.                          161

                Julie Magno Zito, M.D.                         163

                Joseph Glenmullen, M.D.                        164

                Linda Cheslek                                  165

                Jeff Avery                                     167

                Harry Skigis                                   169

                Pamela Wild                                    170

                Karen Barth Menzies                            172

                Amy Coburn                                     174

                Sharon McBride                                 175

                Thomas Moore, M.D.                             178

 

      Pediatric and Adolescent Antidepressant Drug Use

      in the U.S.:

                Gianna C. Rigoni, Pharm.D., M.S.               181

 

      One-Year Post-Exclusivity-Mandated Adverse Event

      Review for Paroxetine and Citalopram:

                Solomon Iyasu, M.D., MPH                       195

 

      Office of Drug Safety Data Resources

      for the Study of Suicidal Events:

                Andrew D. Mosholder, M.D., MPH                 215

 

      Open Public Hearing

                David Fassler, M.D.                            225

                Lawrence Diller                                227

 

      Regulatory History on Antidepressants and

      Suicidality and Update on Current Plans for

      Analysis of Pediatric Suicidality Data:

                Thomas Laughren, M.D.                          230

 

      Suicidality Classification Project:

                Kelly Posner, Ph.D.                            265

 

      Plans for Analysis of Patient Level Data

      for Pediatric Studies:

                Tarek Hammad, M.D., Ph.D., M.Sc., M.S.         273

 

      Open Committee Discussion                                291

 

                                                                 6

 

  1                Call to Order and Opening Remarks

 

  2             DR. RUDORFER:  I am Dr. Matthew Rudorfer,

 

  3   a research psychiatrist at the National Institute

 

  4   of Mental Health, today wearing my hat as Chair of

 

  5   the Advisory Committee.

 

  6             As you settle in, please take this

 

  7   opportunity to put into silent mode your cell

 

  8   phones and any other devices that ring, beep, or

 

  9   play show tunes.

 

 10             I have some official language to read.

 

 11   All committee members and consultants have been

 

 12   provided with copies of background materials from

 

 13   the FDA and with copies of letters from the public

 

 14   that were received by the January 26th deadline.

 

 15   The background materials have been posted on the

 

 16   FDA web site.  Copies of all these materials are

 

 17   available for viewing at the FDA desk outside this

 

 18   room.

 

 19             We have a large table and a full house as

 

 20   you can see and a very important and exciting topic

 

 21   to discuss, so we would like to start with a few

 

 22   rules of order.  FDA relies on its advisory

 

 23   committees to provide the best possible scientific

 

 24   advice available to assist us in a discussion of

 

 25   complex topics.  We understand that issues raised

 

                                                                 7

 

  1   during the meeting may well lead to conversations

 

  2   over breaks or during lunch.

 

  3             However, one of the benefits of an

 

  4   advisory committee meeting is that discussions take

 

  5   place in an open and public forum.  To that end, we

 

  6   request that members of the committees not engage

 

  7   in off-record conversations on today's topic during

 

  8   the breaks and lunch.

 

  9             Whenever there is an important topic to be

 

 10   discussed, there are a variety of opinions.  One of

 

 11   our goals today is for this meeting to be conducted

 

 12   in a fair and open way where every participant is

 

 13   listened to carefully and treated with dignity,

 

 14   courtesy, and respect. Anyone whose behavior is

 

 15   disruptive to the meeting will be asked to leave.

 

 16             We are confident that everyone here is

 

 17   sensitive to these issues and can appreciate that

 

 18   these comments are intended as a gentle reminder.

 

 19   We look forward to a productive and interesting

 

 20   meeting.

 

 21             Just to reiterate a couple of points.

 

 22   This is an unusual meeting in that we have two

 

 23   advisory committees represented here,

 

 24   Psychopharmacologic Drugs and a subcommittee that

 

 25   is equivalent of a Pediatric Drugs Advisory

 

                                                                 8

 

  1   Committee chaired by Dr. Joan Chesney here to my

 

  2   left.

 

  3             Suppose we begin by going around the table

 

  4   for introductions.  Can we start at that end,

 

  5   please.

 

  6                          Introductions

 

  7             DR. TEMPLE:  I am Bob Temple.  I am the

 

  8   Office Director for Office of Drug Evaluation I.

 

  9             DR. KATZ:  Russ Katz, Division Director of

 

 10   the Division of Neuropharmacological Drug Products,

 

 11   FDA.

 

 12             DR. LAUGHREN:  Tom Laughren, Psychopharm

 

 13   Team Leader in the Neuropharm Division.

 

 14             DR. MURPHY:  Dianne Murphy, Office

 

 15   Director, Office of Counterterrorism and Pediatric

 

 16   Drug Development.

 

 17             DR. CUMMINS:  Susan Cummins, Medical Team

 

 18   Leader with the Division of Pediatric Drug

 

 19   Development.

 

 20             DR. TRONTELL:  Anne Trontell, Deputy

 

 21   Director, Office of Drug Safety.

 

 22             DR. FUCHS:  Susan Fuchs, member of the

 

 23   Pediatric Subcommittee of the Anti-Infective Drugs

 

 24   Advisory Committee.

 

 25             DR. FINK:  Bob Fink, pediatric

 

                                                                 9

 

  1   pulmonologist, Dayton, Ohio.

 

  2             DR. ORTIZ:  Irene Ortiz, geriatric

 

  3   psychiatrist, Albuquerque VA and the University of

 

  4   New Mexico.

 

  5             DR. LESLIE:  Lauren  Leslie, behavioral

 

  6   and developmental pediatrician and health services

 

  7   researcher in San Diego.

 

  8             DR. LEON:   Andrew Leon, Professor of

 

  9   Biostatistics and Psychiatry at Cornell Medical

 

 10   College.

 

 11             DR. GOODMAN:  Wayne Goodman, Professor and

 

 12   Chairman, Department of Psychiatry at the

 

 13   University of Florida.

 

 14             DR. PFEFFER:  Cynthia Pfeffer, Adolescent

 

 15   Psychiatrist and Professor of Psychiatry at Weill

 

 16   Medical College of Cornell University.

 

 17             DR. GORMAN:  Rich Gorman, pediatrician in

 

 18   private practice in Ellicott City and member of the

 

 19   Pediatric Advisory Subcommittee.

 

 20             DR. GLODE:  Mary Glode, Professor of

 

 21   Pediatrics, Pediatric Infectious Disease Specialist

 

 22   at Children's Hospital, University of Colorado at

 

 23   Denver.

 

 24             DR. HUDAK:  Mark Hudak, neonatologist and

 

 25   Professor of Pediatrics, University of Florida at

 

                                                                10

 

  1   Jacksonville, and member of the Pediatric

 

  2   Subcommittee.

 

  3             DR. MALONE:  Richard Malone, child

 

  4   psychiatrist, Drexel University, College of

 

  5   Medicine, and I am a member of the Psychopharm

 

  6   Advisory Committee.

 

  7             DR. SANTANA:  Victor Santana, pediatric

 

  8   hematologist/oncologist, St. Jude's Children's

 

  9   Research Hospital and University of Tennessee at

 

 10   Memphis, Tennessee.

 

 11             MS. PATEL:  Anuja Patel, Executive

 

 12   Secretary, Advisors and Consultants Staff.

 

 13             DR. RUDORFER:  Dr. Matthew  Rudorfer,

 

 14   Acting Chief, Adult Interventions Branch, National

 

 15   Institute of Mental Health and Chair of the

 

 16   Psychopharmacologic Drugs Advisory Committee.

 

 17             DR. CHESNEY:  Joan Chesney, Professor of

 

 18   Pediatrics at the University of Tennessee in

 

 19   Memphis, and at St. Jude's Children Research

 

 20   Hospital, and the Pediatric Subcommittee.

 

 21             DR. McGOUGH:  Jim McGough, Associate

 

 22   Professor in Child and Adolescent Psychiatry at

 

 23   UCLA and member of the Psychopharm Drugs Advisory

 

 24   Committee.                                DR.

 

 25   GRADY-WELIKY:  Tana Grady-Weliky, Associate

 

                                                                11

 

  1   Professor of Psychiatry at the University of

 

  2   Rochester, School of Medicine and Dentistry, and

 

  3   member of the Psychopharm Advisory Committee.

 

  4             DR. WANG:  Philip Wang, psychiatrist and

 

  5   epidemiologist, Harvard Medical School.

 

  6             DR. O'FALLON:  Judith O'Fallon, recently

 

  7   retired from the Cancer Center Statistics Unit of

 

  8   the Mayo Clinic.  I am a member of the Pediatric

 

  9   Subcommittee.

 

 10             DR. NELSON:  Robert Nelson, Pediatric

 

 11   Critical Care Medicine at the Children's Hospital,

 

 12   Philadelphia.

 

 13             DR. ANDREWS:  Elizabeth Andrews,

 

 14   pharmaco-epidemiologist at Research Triangle

 

 15   Institute and the University of North Carolina

 

 16   Centers for Educational Research and Therapeutics,

 

 17   and I am a consultant.

 

 18             MS. GRIFFITH:  Gail Griffith.  I am a

 

 19   writer.  I live in Washington.  I am the Patient

 

 20   Representative, a parent of a child suffering from

 

 21   MDD, and a patient who suffers from MDD.

 

 22             DR. FOST:  Norm Fost, Professor of

 

 23   Pediatrics and Director of the Bioethics Program at

 

 24   the University of Wisconsin.

 

 25             MS. BRONSTEIN:  Jean Bronstein, nurse with

 

                                                                12

 

  1   a background in psychiatry, retired, and I am the

 

  2   Consumer Representative for Psychopharm.

 

  3             DR. EBERT:  Steve Ebert, pharmacist and

 

  4   infectious diseases, Professor of Pharmacy at the

 

  5   University of Wisconsin/Madison, member of the

 

  6   Pediatric Subcommittee.

 

  7             DR. DANFORD:  David Danford, Professor of

 

  8   Pediatrics and cardiologist in the Joint Section of

 

  9   Pediatric Cardiology, University of Nebraska,

 

 10   Creighton University, member of the Pediatric

 

 11   Subcommittee.

 

 12             DR. PINE:  Daniel Pine, child

 

 13   psychiatrist, National Institute of Mental Health,

 

 14   Intramural Research Program.

 

 15             DR. MALDONADO:  Samuel Maldonado, Chair of

 

 16   the Pediatric Working Group at PhRMA  and member of

 

 17   the Pediatric Subcommittee.

 

 18             DR. MEHTA:  Dilip Mehta from New York.  I

 

 19   am the Industry Representative on the

 

 20   Psychopharmacologic Advisory Committee.       

 

 21                                         DR. RUDORFER:

 

 22   Thank you.  Our session today is actually the first

 

 23   of two planned advisory committee meetings convened

 

 24   to address recent concerns about reports of

 

 25   suicidal ideas and behavior developing in some

 

                                                                13

 

  1   children and adolescents during treatment of

 

  2   depression with an SSRI or similar newer

 

  3   antidepressants.

 

  4             Our goal is to gather information from a

 

  5   variety of sources and perspectives to help us

 

  6   understand this complex situation and ultimately to

 

  7   offer the best possible recommendations to the FDA.

 

  8             I would like to thank the many groups,

 

  9   individuals, and families that submitted written

 

 10   statements in advance of this meeting, many of

 

 11   which were quite informative as well as moving.

 

 12             Much of today's meeting will be devoted to

 

 13   a two-part open public hearing during which dozens

 

 14   of people from around and even beyond the country

 

 15   will have the opportunity to present their own

 

 16   personal or professional experiences and ideas

 

 17   about the relative risks and benefits of

 

 18   antidepressant medications in children and

 

 19   adolescents.

 

 20             Although the necessary consideration of

 

 21   the clock will permit only a short time at the

 

 22   microphone for each speaker, I can assure you that

 

 23   the committee welcomes and values input from all

 

 24   viewpoints and feels it essential to our work that

 

 25   all voices be heard.

 

                                                                14

 

  1             Major depression remains an

 

  2   underdiagnosed, understudied, and undertreated

 

  3   serious and even life-threatening mental disorder

 

  4   among thousands of our nation's youth, leading to

 

  5   considerable dysfunction, disability, and

 

  6   heartbreak in many families.

 

  7             I am hopeful that with a fair and

 

  8   open-minded review of the evidence in hand and that

 

  9   still emerging, this advisory committee can

 

 10   constructively address the challenges we all share

 

 11   to assure that interventions for this deadly

 

 12   disorder are available for those young people who

 

 13   desperately need them and that those treatments

 

 14   meet high standards for both effectiveness and

 

 15   safety.

 

 16             Now, I will ask Anuja Patel, of the FDA

 

 17   Center for Drug Evaluation and Research, to review

 

 18   some of the ground rules for the open public

 

 19   hearing.

 

 20             MS. PATEL:  Good morning.  As you know, we

 

 21   have a very full open public hearing today and in

 

 22   the interest of both fairness and efficiency, we

 

 23   are running it by some strict rules.

 

 24             Due to the vast majority of requests by

 

 25   registered speakers to speak in the morning

 

                                                                15

 

  1   session, we will lengthen the morning session of

 

  2   open public hearing and shorten the afternoon

 

  3   session accordingly.

 

  4             To make the transitions between speakers

 

  5   more efficient, all speakers will be using the

 

  6   podium in front of the audience.  Each speaker has

 

  7   been given their number and the order of

 

  8   presentation, and when the person ahead of you is

 

  9   speaking, we ask that you move to the nearby next

 

 10   speaker chair.

 

 11             Individual presenters and families have

 

 12   been allotted two minutes for their presentations.

 

 13   The three combined groups' presentations have been

 

 14   allotted three minutes.  We will be using a timer

 

 15   and speakers who run over their time limit will

 

 16   find that the microphone is no longer working.

 

 17             We apologize for the need for the strict

 

 18   rules, but we wanted to give as many people as

 

 19   possible an opportunity to participate.  Thank you

 

 20   for your cooperation.

 

 21             I will now state the Conflict of Interest

 

 22   Statement for the record.

 

 23                  Conflict of Interest Statement

 

 24             The following announcement addresses the

 

 25   issue of conflict of interest with respect to this

 

                                                                16

 

  1   meeting and is made a part of the record to

 

  2   preclude even the appearance of such at this

 

  3   meeting.

 

  4             Based on the agenda, it has been

 

  5   determined that the topics of today's meeting are

 

  6   issues of broad applicability and there are no

 

  7   products being approved at this meeting.  Unlike

 

  8   issues before a committee in which a particular

 

  9   product is discussed, issues of broader

 

 10   applicability involve many industrial sponsors and

 

 11   academic institutions.

 

 12             All Special Government Employees have been

 

 13   screened for their financial interests as they may

 

 14   apply to the general topics at hand.  To determine

 

 15   if any conflict of interest existed, the Agency has

 

 16   reviewed the agenda and all relevant financial

 

 17   interests reported by the meeting participants.

 

 18             The Food and Drug Administration has

 

 19   granted general matter waivers to the Special

 

 20   Government Employees participating in this meeting

 

 21   who require a waiver under Title 18, United States

 

 22   Code, Section 208.

 

 23             A copy of the waiver statements may be

 

 24   obtained by submitting a written request to the

 

 25   Agency's Freedom of Information Office, Room 12A-30

 

                                                                17

 

  1   of the Parklawn Building.

 

  2             Because general topics impact so many

 

  3   entities, it is not prudent to recite all potential

 

  4   conflict of interests as they apply to each member

 

  5   and consultant and guest speaker.

 

  6             FDA acknowledges that there may be

 

  7   potential conflicts of interest, but because of the

 

  8   general nature of the discussion before the

 

  9   committee, these potential conflicts are mitigated.

 

 10             With respect to FDA's invited industry

 

 11   representatives, we would like to disclose that Dr.

 

 12   Dilip Mehta and Dr. Samuel Maldonado are

 

 13   participating in this meeting as industry

 

 14   representatives acting on behalf of regulated

 

 15   industry.  Dr. Mehta is retired from Pfizer and Dr.

 

 16   Maldonado is employed by Johnson & Johnson.

 

 17             In addition, FDA would also like to note

 

 18   that one member of the Psychopharmacologic Drugs

 

 19   Advisory Committee, Andrew Leon, and an FDA

 

 20   speaker, David Shaffer, were members of the

 

 21   American College of Neuropsychopharmacology ACMP

 

 22   Task Force that has recently issued a preliminary

 

 23   report on SSRIs and suicidal behavior in youth.

 

 24             This task force reviewed published and

 

 25   unpublished data from controlled trials in youth,

 

                                                                18

 

  1   data from epidemiological studies, and data from

 

  2   autopsy studies.

 

  3             Based on their preliminary review, they

 

  4   concluded that the available evidence does not

 

  5   suggest that SSRIs increase the risk of suicidal

 

  6   behavior in youth and with depression, however,

 

  7   they acknowledge that their conclusions are

 

  8   preliminary and they recommend that the pertinent

 

  9   data available to pharmaceutical companies and FDA

 

 10   be rapidly made available to ACMP and others, so

 

 11   that they may be independently evaluated.

 

 12             In the event that the discussions involve

 

 13   any other products or firms not already on the

 

 14   agenda for which FDA participants have a financial

 

 15   interest, the participants' involvement and their

 

 16   exclusion will be noted for the record.

 

 17             With respect to all other participants, we

 

 18   ask in the interest of fairness that they address

 

 19   any current or previous financial involvement with

 

 20   any firm whose product they may wish to comment

 

 21   upon.

 

 22             Thank you.

 

 23             DR. RUDORFER:  Thank you.

 

 24             To put the meeting in context, I would now

 

 25   like to turn to Dr. Russell Katz, Director of the

 

                                                                19

 

  1   FDA Division of Neuropharmacologic Drug Products,

 

  2   who will provide a brief overview of the background

 

  3   leading to today's deliberations and the likely

 

  4   next steps.

 

  5                        Overview of Issues

 

  6             DR. KATZ:  Thank you, Dr. Rudorfer, and

 

  7   good morning.  I would like to also add my welcome

 

  8   to all of you here for this joint meeting of the

 

  9   Pediatric Subcommittee of the Anti-Infective Drugs

 

 10   Advisory Committee and the Psychopharmacologic

 

 11   Drugs Advisory Committee.

 

 12             In particular, I would like to welcome our

 

 13   invited guests who are not members of the

 

 14   committee, but who have graciously agreed to help

 

 15   us grapple with the difficult problem that we bring

 

 16   to you today.

 

 17             As you know, we are here to discuss with

 

 18   you an issue of enormous importance and interest,

 

 19   namely, the relationship, if any, between treatment

 

 20   of pediatric patients with antidepressant drugs and

 

 21   suicidal behavior.

 

 22             This has been an issue of extreme

 

 23   complexity and we are here both to inform you of

 

 24   our efforts to date to examine the question and our

 

 25   plans for further examination of the data, as well

 

                                                                20

 

  1   as to ask for your comments and advice about these

 

  2   plans.

 

  3             We come to you at this time for several

 

  4   reasons. Under current law, the Agency is required

 

  5   to present postmarketing adverse event data to the

 

  6   Pediatric Subcommittee for the first year of

 

  7   marketing for those drugs granted market

 

  8   exclusivity under the pediatric exclusivity

 

  9   provisions of the Act.

 

 10             At this time, therefore, the Agency is

 

 11   meeting its obligation under the law to present

 

 12   this data for Paxil and Celexa.  More importantly,

 

 13   however, given the intense interest in the Agency's

 

 14   efforts to examine the question of antidepressant

 

 15   use in pediatric patients and suicidal behavior, we

 

 16   concluded that it would be appropriate to inform

 

 17   you about these latter efforts at this time, as

 

 18   well.

 

 19             As you know, we most recently became aware

 

 20   of a potential signal of concern during the review

 

 21   of the controlled trial data for Paxil.  In the

 

 22   course of that review, we became aware that the

 

 23   sponsor had categorized some events that could have

 

 24   represented suicidal behavior or suicidal thinking

 

 25   using a description that seemed somewhat

 

                                                                21

 

  1   inappropriate.

 

  2             We asked them to clarify their

 

  3   presentation of the data, and their response raised

 

  4   a concern that such a signal existed.  Based on

 

  5   these concerns, the Agency issued a public

 

  6   statement in June of last year recommending that

 

  7   this drug not be used to treat pediatric patients

 

  8   with depression, but based on the Paxil data and

 

  9   the problem of idiosyncratic characterization of

 

 10   events of potential concern identified in that

 

 11   application, we asked the sponsors of the other

 

 12   antidepressant drugs to search their controlled

 

 13   trial databases in a more formal way to identify

 

 14   potential cases of suicidal behavior.

 

 15             Our review of their responses resulted in

 

 16   a second Agency statement that alerted

 

 17   practitioners to a similar potential signal for

 

 18   other drugs in this class, and recommended that

 

 19   these drugs be used with caution in these patients.

 

 20             Our continued review of these data,

 

 21   however, convinced us that the data submitted from

 

 22   the various companies involved may not have been

 

 23   collected or reported to us in a form that would

 

 24   permit us to adequately evaluate the potential

 

 25   relationship between these drugs and suicidal

 

                                                                22

 

  1   behavior.

 

  2             Indeed, we became convinced that with the

 

  3   data before us at that time, we could not

 

  4   adequately answer the question of whether there was

 

  5   such a relationship for any specific drug or

 

  6   whether there were any differences between drugs.

 

  7             You will hear in greater detail later the

 

  8   deficiencies with these data as previously

 

  9   submitted and why we have therefore continued to

 

 10   work with the sponsors involved to submit to us

 

 11   data in the form that will permit us to adequately

 

 12   and comprehensively address the critical question

 

 13   before us.

 

 14             It is because we are not yet able to do

 

 15   this that we could not present definitive analyses

 

 16   at this time.  It is absolutely critical, in our

 

 17   view, that we make every effort to provide the best

 

 18   answer possible to this question. The wrong answer

 

 19   in either direction, prematurely arrived at, could

 

 20   have profound negative consequences for the public

 

 21   health.

 

 22             However, we now believe that we have

 

 23   obtained from the sponsors all of the relevant data

 

 24   collected during the trials, presented in a

 

 25   standardized manner that will permit us to perform

 

                                                                23

 

  1   analyses that will give us the best possible chance

 

  2   to address this question.

 

  3             Before we embark upon these analyses,

 

  4   however, we are taking this opportunity to inform

 

  5   you and the public about the problems we have

 

  6   encountered in trying to answer this question, how

 

  7   we have attempted to address those problems, and to

 

  8   describe our plans for analyzing the data.

 

  9             We are primarily interested in your views

 

 10   about our proposed approaches to the data and are

 

 11   eager to hear if you believe we should request

 

 12   additional data from the sponsors and whether you

 

 13   believe we should perform additional analyses

 

 14   beyond those we will describe to you later today.

 

 15             In our efforts to further evaluate the

 

 16   data, we have enlisted the help of outside experts

 

 17   with particular expertise in the issue of pediatric

 

 18   depression and suicide, and in particular, we have

 

 19   enlisted a group from Columbia University, who will

 

 20   objectively reclassify potential cases of

 

 21   suicidality from all the drug development programs,

 

 22   so that we may move forward with our more

 

 23   definitive analyses.  You will hear about this from

 

 24   Dr. Kelly Posner in more detail later.

 

 25             We will also present the postmarketing

 

                                                                24

 

  1   adverse event data for the drugs in question, but

 

  2   as you will hear, and for the reasons you will

 

  3   hear, we do not believe that this data can

 

  4   reasonably inform our judgment about any

 

  5   relationship between these drugs and suicidal

 

  6   behavior.

 

  7             It is the controlled trial data that we

 

  8   believe is best able to help us provide an adequate

 

  9   answer to this question, but as you have heard, and

 

 10   you will hear throughout today's presentations, we

 

 11   do not believe that this data until now has been

 

 12   provided to us in a way that would permit us to

 

 13   interpret it fully.

 

 14             It should be noted that this view of the

 

 15   data has not been a unanimous one among Agency

 

 16   staff.  Some within the Agency have examined the

 

 17   data and concluded that the data, as currently

 

 18   submitted, do permit definitive analyses and that

 

 19   these analyses support the conclusion that this

 

 20   class of drugs is associated with a risk of

 

 21   suicidal behavior in pediatric patients.

 

 22             However, the staff of the

 

 23   Neuropharmacological Drugs Division has examined

 

 24   the individual cases reported by the sponsors that

 

 25   allegedly represent suicidal behavior, and we are

 

                                                                25

 

  1   convinced that the categorization of these events,

 

  2   as performed idiosyncratically by the individual

 

  3   sponsors, is not entirely reliable.

 

  4             Examples of these categorizations will be

 

  5   presented to you later today, and we are confident

 

  6   that this conclusion will become clear to you.

 

  7             Further, the pattern of these potential

 

  8   signals is also difficult to understand, for

 

  9   example, arising from one single study out of

 

 10   several similarly size studies for a given drug.

 

 11   This unusual pattern gives us further reason to

 

 12   more closely examine the data.

 

 13             We are, of course, aware that there is

 

 14   great concern among the families of children and

 

 15   adolescents with depression about whether or not

 

 16   these drugs can be used safely.  For them, I am

 

 17   sure answering this question has already taken too

 

 18   long.

 

 19             We, too, are frustrated with the time it

 

 20   has taken to come to a definitive answer to this

 

 21   question.  Indeed, we had originally hoped to be

 

 22   able to present to you today more definitive

 

 23   analyses and conclusions, however, as I have

 

 24   described, closer examination of the data at each

 

 25   step of our analyses convinced us that it would be

 

                                                                26

 

  1   premature to arrive at a conclusion without

 

  2   additional work, the plans for which we will

 

  3   present to you later today.

 

  4             We are firmly convinced that we serve no

 

  5   one's goals or needs by rushing to a judgment that

 

  6   has not considered all reasonable sides to the

 

  7   question.  We are committed to, and fully expect

 

  8   to, come back to the committee in late summer with

 

  9   the results of the analyses we will discuss today.

 

 10             At that time, we expect to be able to

 

 11   present the best possible answer that the current

 

 12   data can provide to the question of whether or not

 

 13   any of these drugs, all of these drugs, or none of

 

 14   these drugs increase the risk of suicidality in

 

 15   pediatric patients.

 

 16             With that as an introduction, I will turn

 

 17   it back to Dr. Rudorfer.

 

 18             DR. RUDORFER:  Thank you, Dr. Katz.

 

 19             We will now hear from Dr. Dianne Murphy,

 

 20   Director of FDA's Office of Counterterrorism and

 

 21   Drug Development, who will speak about the

 

 22   Pediatric Drug Development Program.

 

 23                Pediatric Drug Development Program

 

 24             DR. MURPHY:  Welcome.  Thank you very much

 

 25   for taking time to make this endeavor an important

 

                                                                27

 

  1   part of your scientific and academic life.  We hold

 

  2   your advice very important and look very much

 

  3   forward to your discussion.

 

  4             [Slide.]

 

  5             I am going to ask you to step back for a

 

  6   moment. My comments are not going to focus directly

 

  7   on the topic of depression or the therapies for

 

  8   that.  The goal of my presentation is to provide

 

  9   you some background on pediatric drug development

 

 10   because I think you will see that is the process

 

 11   that has brought us some of this data and we need

 

 12   to make sure everybody understands how this

 

 13   evolved.

 

 14             It is also an example of watch out what

 

 15   you ask for because we now finally, in the last few

 

 16   years, are beginning to get the kind of information

 

 17   that we wanted for a long time to be able to

 

 18   understand how we could better treat children with

 

 19   the therapies that we have.

 

 20             Of course, we will be reviewing FDA's

 

 21   specific responsibilities during these activities.

 

 22             [Slide.]

 

 23             Acronyms.  Throughout the day, you will be

 

 24   hearing these potentially.  You have FDAMA.  That

 

 25   is the Food and Drug Administration Modernization

 

                                                                28

 

  1   Act.  This is important because this is the

 

  2   legislative initiative that provided the Agency

 

  3   with the ability to provide an incentive that has

 

  4   been a tremendous -- I call it the engine that has

 

  5   really been driving this process for being able to

 

  6   develop information on how to use these products in

 

  7   children.

 

  8             Remember, before this, most children, if

 

  9   it was not a pediatric disease like otitis media,

 

 10   these products were not being studied in children,

 

 11   and each child was an n of 1 in which we did not

 

 12   learn anything, and that was not an approach we

 

 13   thought useful.  That's FDAMA.

 

 14             Best Pharmaceuticals for Children, renewal

 

 15   of the legislation basically expanding not only the

 

 16   legislative mandate to look at products that have

 

 17   patents remaining where the incentive will work,

 

 18   but a process which mandates FDA and NIH to work

 

 19   together to develop the same sort of data for

 

 20   products that are older and would not benefit

 

 21   because that was an area that was not being

 

 22   developed.

 

 23             The way that is done is important to

 

 24   understand because it is done via what is called

 

 25   the written request in which FDA -- and this is

 

                                                                29

 

  1   distinctive from most other drug development -- FDA

 

  2   determines what the public health need is and

 

  3   issues a written request defining the studies that

 

  4   they think need to be done, so that we can better

 

  5   understand how to dose children or if it works in

 

  6   children, or what are the distinctive adverse

 

  7   events that occur in children, because as we all

 

  8   know, the variability between a preemie and a

 

  9   fullback is tremendous, and we have that in

 

 10   children, and evolving developmental processes.

 

 11             PREA was the recently legislation that in

 

 12   essence said yes, FDA, you have the authority to

 

 13   require that if a sponsor submits an application

 

 14   for a disease -- I am going to call it indication

 

 15   throughout the rest of this -- for an indication

 

 16   that exists in children for which this product will

 

 17   likely be used, you are to study it in children

 

 18   also.  You are not just to market it for adults.

 

 19             This proposed pediatric study is a process

 

 20   that applies to the written request, which if

 

 21   industry is interested in studying a product, they

 

 22   can submit it to FDA, and we can look at that.

 

 23             That is important because what you need to

 

 24   understand is that this whole exclusivity process

 

 25   is voluntary, so it is up to the sponsor whether

 

                                                                30

 

  1   they want to participate or not.  This process is

 

  2   not.

 

  3             [Slide.]

 

  4             The interesting thing about pediatric drug

 

  5   development is that many of the legislation that

 

  6   has developed has developed because of misfortunes

 

  7   and severe tragedies that have happened in

 

  8   children, and yet every time new legislation would

 

  9   be mandated, it would apply to adults, and not to

 

 10   children.

 

 11             Many of you have heard this talk, so I am

 

 12   just quickly putting these up here to remind

 

 13   everybody.

 

 14             [Slide.]

 

 15             We have for decades been trying to have

 

 16   products that are being used in children studied,

 

 17   and this is just to give you really the benchmarks,

 

 18   starting in the '70s, in which the Academy of

 

 19   Pediatrics issued a statement saying we ought to be

 

 20   studying these products we are using in children,

 

 21   why do we think that children are going to be less

 

 22   variable than adults.  All reason and information

 

 23   would say they are going to be more variable, and

 

 24   we need to.

 

 25             The Agency actually issued a statement

 

                                                                31

 

  1   saying we think children should be studied, and we

 

  2   would like you to conduct two adequate trials also

 

  3   for children, to evaluate the safety and efficacy

 

  4   in children.

 

  5             What happened was not much, and as

 

  6   everybody has heard, the majority of products were

 

  7   not studied in children until really here.

 

  8             In 1994, FDA published a regulation which

 

  9   basically said we understand that there are times

 

 10   in which you can extrapolate efficacy only.  If the

 

 11   disease is similar enough, the pathophysiology, and

 

 12   the expected response have been defined well

 

 13   enough, that you might be able to extrapolate

 

 14   efficacy, hoping to incentivize in a way the

 

 15   interest in developing information and conducting

 

 16   trials in children.  Safety and dose finding were

 

 17   still trials that you would need to conduct in

 

 18   children.

 

 19             Again, minimal response.  So, bottom line,

 

 20   the first incentive program was the major push.

 

 21   The FDA published a regulation, which was then

 

 22   enjoined by a court saying we didn't have the

 

 23   authority to require it, so Congress came back in

 

 24   2003 and said, yes, FDA, you do.

 

 25             So, right now here are the two things that

 

                                                                32

 

  1   are driving pediatric drug development, so that we

 

  2   can better understand how to use these products in

 

  3   children.

 

  4             [Slide.]

 

  5             It has been a tremendous response.  This

 

  6   is just simulated to exclusivity.  We have received

 

  7   over 300 proposals.  You could have counted the

 

  8   number of products developed on your fingers and

 

  9   toes before this that weren't primarily pediatric

 

 10   diseases.

 

 11             We have issued over 283 written requests

 

 12   where FDA has determined what needs to be developed

 

 13   in the way of studies, and has issued sponsors'

 

 14   requests. This is updated from your handout, by the

 

 15   way, these numbers are slightly different because

 

 16   we updated it for the slides.

 

 17             The important thing about exclusivity

 

 18   determinations, it means that over 100 products

 

 19   have been brought in with the studies that have

 

 20   been requested, and you are discussing some of

 

 21   those today, with the type of information that

 

 22   helps us better understand.

 

 23             We have an entire one-hour talk on some of

 

 24   the very significant findings that have been

 

 25   developed, that we have discovered in this process.

 

                                                                33

 

  1   Today is another example of we are finding out what

 

  2   more information we need if we are going to

 

  3   properly use these products.

 

  4             I only put these numbers up because once

 

  5   exclusivity is granted, you can see some were

 

  6   denied, even though it may have been denied, it

 

  7   still could have been approved.  It just meant that

 

  8   they didn't meet the terms completely that we asked

 

  9   for.

 

 10             There are now 63 new labels, so products

 

 11   that are being used in children, there are now 63

 

 12   of them that have new labels, new important dosing

 

 13   and safety information in them including

 

 14   information that says they don't work in kids with

 

 15   these studies.

 

 16             [Slide.]

 

 17             These are the products that were mandated,

 

 18   not the individual products, but the process that

 

 19   was mandated by the Best Pharmaceuticals, the BPCA.

 

 20   I point this out because one of these, our set of

 

 21   data you are going to hear today is the result of

 

 22   BPCA saying FDA, one year after a product has been

 

 23   granted exclusivity, you will follow all of the

 

 24   adverse events that are reported for that product,

 

 25   and you will present it to the Pediatric Advisory

 

                                                                34

 

  1   Subcommittee that will soon be a full committee,

 

  2   and that this is an area which BPCA wanted to make

 

  3   sure that additional attention was paid to the

 

  4   process of reviewing what happens.

 

  5             The thing to understand about that is that

 

  6   a product could be approved way back 10 years ago,

 

  7   and it could then be studied later in its life for

 

  8   pediatrics, so that the one-year post-safety

 

  9   assessment is at varying stages of these different

 

 10   products, they are not all the same, and the

 

 11   Division has tried to standardize that for you

 

 12   today in looking at the safety assessments at more

 

 13   standardized times because each product is coming

 

 14   in at a different time.

 

 15             [Slide.]

 

 16             The only other thing I really wanted to

 

 17   point out to everybody, to bring us back to the

 

 18   topic at hand today, is that this drug development

 

 19   process that has begun to occur really since 1998,

 

 20   five, six years, has brought forth not only new

 

 21   information that challenges some of our

 

 22   preconceived thoughts about safety and how children

 

 23   respond, it has been a tremendous bounty of

 

 24   information because children are finally getting

 

 25   studied.

 

                                                                35

 

  1             We are beginning to have to figure out how

 

  2   do you measure that endpoint in children.  That

 

  3   type of science was not being developed.  We are

 

  4   also dealing with the ethical issues that come up,

 

  5   that are different for kids who cannot consent, so

 

  6   this is a whole different process, and I just want

 

  7   to make sure that you all knew that we have brought

 

  8   various ethical issues to the committees, and we

 

  9   have a wonderful cadre of ethicists who are Special

 

 10   Government Employees, who work with the Pediatric

 

 11   Advisory Subcommittee, who attended these meetings

 

 12   and advised us on such topics as should children be

 

 13   enrolled in trials in which they are not going to

 

 14   receive direct benefit, should children be enrolled

 

 15   in placebo-controlled trials, should children who

 

 16   are especially vulnerable -- most people think of

 

 17   children as a vulnerable population, but in truth,

 

 18   there are subsets, subpopulations that are even

 

 19   more vulnerable, and this was a population of

 

 20   children with CP, how do you develop a product in

 

 21   that population.  These are difficult issues.

 

 22             [Slide.]

 

 23             This is, quickly, and I am not going to go

 

 24   over every one of these, but to give you an idea of

 

 25   the broad array of products that are being

 

                                                                36

 

  1   developed in children and the questions that have

 

  2   come up.

 

  3             Actually, Neuropharm, the Division of

 

  4   Neuropharmacological Drug Products, has brought a

 

  5   number of these issues to the committee, including

 

  6   how do we develop pediatric products -- NIMH also

 

  7   participated in this meeting -- from such issues as

 

  8   -- also, this was another Neuropharm Advisory

 

  9   Committee meeting with the Pediatric Committee --

 

 10   chronic hepatitis, reflux in infants, HIV drugs,

 

 11   how do you approach the whole field of developing a

 

 12   product that may be put in almost every newborn who

 

 13   develops hyperbilirubinemia, tremendous issues,

 

 14   long term study issues.

 

 15             Again, more, what do you do about some of

 

 16   these products.  Most of our products' safety

 

 17   databases are collected on weeks, usually, maybe

 

 18   months, but certainly not years, what do you do

 

 19   with products that we know can potentially suppress

 

 20   your adrenal axis or products that we know can be

 

 21   oncogenic, but have to be used.

 

 22             [Slide.]

 

 23             Some of the ongoing lessons that we have

 

 24   learned during this process -- which we think is a

 

 25   positive process, it is much better than ignorance

 

                                                                37

 

  1   -- it is that children are even more variable than

 

  2   we really thought.

 

  3             We are finding, for certain classes, you

 

  4   may have to have dosing based on clearance in three

 

  5   different age groups that is very different, and it

 

  6   is not just the preemies, it is not just the

 

  7   neonates.  It is actually children of all ages,

 

  8   from adolescence, preschool, et cetera.

 

  9             Adverse reactions that are

 

 10   pediatric-specific are being defined.  Clearly,

 

 11   growth is one everybody would expect would be

 

 12   defined, that we are finding that products, and

 

 13   Prozac was an example of that, are having an effect

 

 14   on growth.  But there are many other products that

 

 15   we are beginning to look now, and beginning to look

 

 16   in a more systematic way, that we are finding that

 

 17   they do have an effect on growth.

 

 18             But there are other issues - school

 

 19   behavior problem, other products where aggression

 

 20   and behavioral changes have been seen.  So, this is

 

 21   a very important area that we are trying to look at

 

 22   as we develop these products.

 

 23             Trial designs are being modified as we

 

 24   learn, and I think that is probably why we are here

 

 25   today.  We are learning.  We take the best

 

                                                                38

 

  1   knowledge we have, we get the best experts, we

 

  2   issue the type of study we think will be the best,

 

  3   and sometimes something happens in the meantime,

 

  4   more data becomes available, we need to update

 

  5   that, or what we thought we were going to be able

 

  6   to evaluate didn't turn out to be as valuable as

 

  7   something else in the study.

 

  8             We learn from these studies.  Remember,

 

  9   there is a huge amount of science that has not been

 

 10   developed, that is now being developed for

 

 11   children, and, as I said, the ethical issues have

 

 12   to be reassessed from the pediatric perspective.

 

 13             [Slide.]

 

 14             I just got the signal that my time is up,

 

 15   so I will leave you with the general principles

 

 16   that we have developed from the International

 

 17   Conference on Harmonization on how one should

 

 18   approach the whole process involving children in

 

 19   trials, and this is a group that involves European

 

 20   nations, Japan and the United States, and I think

 

 21   that it is a shared responsibility.  That is why we

 

 22   thank you for being here today.  Thank you.

 

 23             [Slide.]

 

 24             This is where you can go onto the web.

 

 25   There is a tremendous amount of information posted

 

                                                                39

 

  1   on pediatric numbers, stats, and studies.

 

  2             Thank you.

 

  3             DR. RUDORFER:  Thank you, Dr. Murphy.

 

  4             As Dr. Katz pointed out, an important way

 

  5   to put issues of drug safety in context is to

 

  6   understand more about the disorder being treated,

 

  7   so we are pleased to have a couple of experts in

 

  8   the area of depression in young people to address

 

  9   us on the latest understanding of this complicated

 

 10   disorder.

 

 11             First, from Weill Medical College of

 

 12   Cornell University, we are pleased to have Dr.

 

 13   Cynthia Pfeffer, who will address Pediatric

 

 14   Depression and its Treatment.

 

 15              Pediatric Depression and its Treatment

 

 16             DR. PFEFFER:  I want especially to provide

 

 17   an overview of pediatric depression, which in fact

 

 18   is a major mental health problem in the United

 

 19   States and probably worldwide.

 

 20             [Slide.]

 

 21             There is a tremendous need to develop

 

 22   treatments for these problems and also prevention

 

 23   efforts primarily because these disorders,

 

 24   particularly major depressive disorder, dysthymic

 

 25   disorder, and for that matter, other mood disorders

 

                                                                40

 

  1   are very prevalent and recurrent, they have high

 

  2   rates of morbidity and comorbidity, they are often

 

  3   accompanied by very poor psychosocial outcomes for

 

  4   children and adolescents.  They are associated with

 

  5   high risk for suicide and also for substance abuse.

 

  6             [Slide.]

 

  7             There are a number of problems which I

 

  8   will touch on in my talk in reducing major

 

  9   depressive disorder in children and adolescents,

 

 10   and these include problems in actually diagnosing

 

 11   children and adolescents.  There are developmental

 

 12   variations that need to be considered.

 

 13             There is a complexity of factors that are

 

 14   associated with the clinical course of children who

 

 15   have such mood disorders and a need for specificity

 

 16   of treatments.

 

 17             [Slide.]

 

 18             Epidemiologically, we know that the

 

 19   prevalence of major depressive disorder in children

 

 20   who are prepubertal is approximately 2 percent, and

 

 21   it increases in adolescents to a rate of between 4

 

 22   and approximately 8 percent.

 

 23             The male-to-female ratio for younger

 

 24   people, prepubertal children, is about equal, but

 

 25   in adolescents, females outnumber males who have

 

                                                                41

 

  1   major depression 2 to 1.

 

  2             By the time a youngster reaches the age of

 

  3   18, there is approximately a 20 percent prevalence

 

  4   rate of those who are depressed, who show major

 

  5   depression, and since prior to World War II, each

 

  6   successive generation seems to have a higher risk

 

  7   for major depressive disorder.

 

  8             If we look at dysthymia, the prevalence

 

  9   rate is somewhat lower although something to be

 

 10   concerned about, with the highest rate of

 

 11   approximately 2 percent in children, and in

 

 12   adolescents, ranging from almost 2 to 8 percent.

 

 13   Dysthymia is a condition that is often

 

 14   under-recognized.

 

 15             [Slide.]

 

 16             There are a number of complexities in

 

 17   diagnosing major depression in children and

 

 18   adolescents.  These include an overlap of a variety

 

 19   of the mood symptoms, and in addition, the symptoms

 

 20   often overlap with comorbid disorders.

 

 21             There are developmental variations in the

 

 22   symptoms and how they are manifest.  There are

 

 23   etiological variations of mood disorders that do

 

 24   involve gene and environmental interactions, and

 

 25   there is a question of whether some of these issues

 

                                                                42

 

  1   are actually spectrum related or categorical

 

  2   disorders.

 

  3             Finally, the effects of medical conditions

 

  4   on the prevalence and incidence of major depression

 

  5   and other mood disorders needs to be considered.

 

  6             [Slide.]

 

  7             The DSM criteria for major depressive

 

  8   disorder involves a pervasive change in mood, which

 

  9   is manifest for at least two weeks by either being

 

 10   depressed or irritable or having a loss of interest

 

 11   in pleasure.

 

 12             There are other symptoms that are

 

 13   necessary in making the diagnosis, that include

 

 14   changes in appetite, weight, sleep, activity

 

 15   levels, concentration, and sometimes

 

 16   indecisiveness, changes in energy level,

 

 17   self-esteem, including worthlessness and excessive

 

 18   guilt, changes in motivation, and recurrent

 

 19   suicidal ideation and acts.

 

 20             These symptoms should represent a change

 

 21   from the child or adolescent's previous functioning

 

 22   and produce impairment.  These symptoms are not

 

 23   attributable to substance abuse, medications, or

 

 24   other psychiatric illness, bereavement, and medical

 

 25   illness.

 

                                                                43

 

  1             [Slide.]

 

  2             There are developmental variations which

 

  3   have been identified.  For example, in children,

 

  4   they tend to have a greater number of symptoms of

 

  5   anxiety, including phobias and separation anxiety,

 

  6   more somatic complaints, and if they do occur,

 

  7   auditory hallucinations.

 

  8             They express irritability with temper

 

  9   tantrums and behavioral problems, and the children

 

 10   tend to have fewer delusions and fewer serious

 

 11   suicide attempts, however, adolescents tend to show

 

 12   more sleep and appetite disturbances, if they

 

 13   occur, delusional thinking, greater degrees of

 

 14   suicidal ideation and acts, and greater impairment

 

 15   of functioning.

 

 16             Compared to adults, however, adolescents

 

 17   have more behavioral problems and fewer

 

 18   neurovegetative symptoms.

 

 19             [Slide.]

 

 20             The diagnostic criteria for dysthymia

 

 21   involves a persistent long-term change in mood

 

 22   which is less intense, but more chronic than major

 

 23   depressive disorder.  These children in adolescence

 

 24   have extensive psychosocial impairment.

 

 25             The depressed mood or irritability occurs

 

                                                                44

 

  1   most of the time during the day for at least one

 

  2   year, and there are at least two other symptoms

 

  3   that are associated in making the diagnosis.  These

 

  4   include again changes in appetite, sleep, lowered

 

  5   self-esteem, problems with concentration, problems

 

  6   with decisionmaking, changes in energy level, and a

 

  7   sense of hopelessness.

 

  8             People who have no symptoms for more than

 

  9   two months at a time, and do not have a major

 

 10   depressive disorder in the first year of

 

 11   disturbance, may be considered to have dysthymic

 

 12   disorder, and these are also youngsters who never

 

 13   had manic or hypomanic episodes.

 

 14             [Slide.]

 

 15             Other symptoms tend to go along with

 

 16   dysthymic disorder.  These include feelings of

 

 17   being unloved, angry outbursts, self-depreciation,

 

 18   somatic complaints, anxiety, and often

 

 19   disobedience.

 

 20             [Slide.]

 

 21             There are a variety of variations that the

 

 22   symptoms of major depressive disorder involve.  For

 

 23   example, psychotic depression, bipolar depressive

 

 24   states, atypical depression, seasonal affective

 

 25   disorder, subclinical or subsyndromal depression,

 

                                                                45

 

  1   and treatment-resistant depression.

 

  2             [Slide.]

 

  3             I will touch on some of these variants now

 

  4   more specifically.  Psychotic depression includes

 

  5   major depressive disorder symptoms that are

 

  6   associated with mood-congruent or incongruent

 

  7   hallucinations and/or delusions, and unlike

 

  8   adolescents, children tend to manifest more

 

  9   hallucinations.

 

 10             Psychotic depression occurs in up to about

 

 11   30 percent of those youngsters with major

 

 12   depressive disorder. It is associated with more

 

 13   severe depression, greater long-term morbidity,

 

 14   resistance to antidepressant monotherapy, a low

 

 15   placebo response, increased risk for bipolar

 

 16   disorder, and a family history of bipolar and

 

 17   psychotic depression.

 

 18             [Slide.]

 

 19             Bipolar depression presents similarly to

 

 20   unipolar depressive disorder.  The risks for

 

 21   bipolar disorder is indicated by psychosis,

 

 22   psychomotor retardation, psychopharmacologically

 

 23   induced hypomania, and a family history of bipolar

 

 24   disorder.

 

 25             Adolescents are likely to have rapid

 

                                                                46

 

  1   cycling or mixed episodes, and an increased suicide

 

  2   risk and difficulty in treatment compliance.  There

 

  3   is a need to rule out bipolar II disorder, which is

 

  4   more prevalent in adolescents and often overlooked

 

  5   and misdiagnosed.

 

  6             [Slide.]

 

  7             Atypical depression has not yet been

 

  8   studied in children and adolescents, and it usually

 

  9   has an onset in adolescence, and it is manifest by

 

 10   increased lethargy, appetite and weight changes,

 

 11   and reactivity to rejection.

 

 12             There is hypersomnia and often

 

 13   carbohydrate craving.  In adults, it tends to be

 

 14   genetically distinct from major depressive

 

 15   disorder.

 

 16             [Slide.]

 

 17             Seasonal affective disorder usually has

 

 18   its onset in adolescence in those living in regions

 

 19   with distinct seasons. The symptoms are similar to

 

 20   those of atypical depression, but are more

 

 21   episodic.  They do not include increase reactivity

 

 22   to rejection.

 

 23             This disorder should be differentiated

 

 24   from depression precipitated by school problems and

 

 25   school stress since it usually overlaps with the

 

                                                                47

 

  1   school calendar.

 

  2             [Slide.]

 

  3             Treatment-resistant depression is not

 

  4   clearly defined for children and adolescents.  It

 

  5   occurs in approximately 6 to 10 percent of

 

  6   depressed children and adolescents who suffer

 

  7   chronic depression.

 

  8             In adults, treatment resistance is defined

 

  9   as patients who have had at least two trials with

 

 10   two different classes of antidepressants which are

 

 11   administered at approximately similar doses for at

 

 12   least six weeks each.

 

 13             [Slide.]

 

 14             Another issue that needs to be thought

 

 15   about in understanding the mood disorders and

 

 16   especially major depression is that they may be

 

 17   affected by the complexity of comorbid disorders

 

 18   which may affect the recognition and diagnosis of

 

 19   major depression, the types and efficacy of

 

 20   treatments, and various psychosocial outcomes.

 

 21             [Slide.]

 

 22             Comorbidity tends to be present in 40 to

 

 23   90 percent of youth with major depression.  Two or

 

 24   more comorbid disorders tend to be present in

 

 25   approximately 20 to 50 percent of youth with major

 

                                                                48

 

  1   depression.

 

  2             Comorbidity in youth with major depression

 

  3   involves dysthymia or anxiety disorders with a rate

 

  4   of approximately 30 to 80 percent, disruptive

 

  5   disorders with a rate of approximately 10 to 80

 

  6   percent, and substance abuse disorders with a rate

 

  7   of approximately 20 to 30 percent.

 

  8             Major depressive onset is usually after

 

  9   the comorbid disorders except for substance abuse

 

 10   in which major depression tends to antedate

 

 11   substance abuse disorders. Conduct problems may be

 

 12   a complication of major depression and may persist

 

 13   after the major depressive episode resolves.

 

 14             Children may manifest separation anxiety

 

 15   comorbid disorders, while adolescents may tend to

 

 16   manifest social phobia, generalized anxiety

 

 17   disorder, conduct disorder, and substance abuse.

 

 18             [Slide.]

 

 19             In terms of differential diagnosis of

 

 20   major depressive disorder, the complexities tend to

 

 21   be with an overlap of symptoms with other

 

 22   nonaffective disorders, such as anxiety states,

 

 23   learning problems, disruptive disorders, and

 

 24   personality disorders and eating disorders.

 

 25             The overlapping symptoms may include poor

 

                                                                49

 

  1   self-esteem, demoralization, poor concentration,

 

  2   irritability, dysphoria, poor sleep, appetite

 

  3   problems, suicidal thoughts, and being overwhelmed.

 

  4             [Slide.]

 

  5             One should consider in the differential

 

  6   diagnosis the nonaffective psychiatric disorders,

 

  7   which include anxiety disorders especially

 

  8   separation anxiety, generalized anxiety, and other

 

  9   anxiety states, disruptive and attention deficit

 

 10   disorders, learning problems, substance abuse,

 

 11   eating disorders especially anorexia nervosa,

 

 12   personality disorders, and premenstrual dysphoric

 

 13   disorder.

 

 14             [Slide.]

 

 15             Another disorder that needs to be

 

 16   considered and understood is an adjustment disorder

 

 17   with depressed mood. This includes a mood change

 

 18   and impairment of functioning within about three

 

 19   months of a stressor, and this does not meet the

 

 20   criteria for major depressive disorder.

 

 21             Adjustment disorder with depressed mood

 

 22   tends to be self-limited, there are less mood

 

 23   disturbances associated with it, fewer symptoms,

 

 24   and no relapse, which is an important issue.

 

 25             Consider other disorders if the symptoms

 

                                                                50

 

  1   last more than six months or meet the criteria for

 

  2   other disorders, for example, dysthymia.

 

  3             [Slide.]

 

  4             General medical conditions may be another

 

  5   complexity in understanding and diagnosing major

 

  6   depressive disorder.  These medical conditions may

 

  7   be accompanied by symptoms of depression.  They may

 

  8   also impact the course of major depressive

 

  9   disorder.

 

 10             Major depression can be diagnosed if the

 

 11   depressive symptoms preceded or are not solely due

 

 12   to the medical condition or to medications used to

 

 13   treat the medical condition.

 

 14             The incidence of major depression tends to

 

 15   be higher in certain medical illnesses.  Chronic

 

 16   illness may affect sleep, appetite, and energy.

 

 17   Guilt, worthlessness, hopelessness, and suicidal

 

 18   ideation are usually not attributed to the medical

 

 19   illness, but do suggest the symptoms of major

 

 20   depressive disorder.

 

 21             Medical conditions that are often

 

 22   associated with major depressive disorder include

 

 23   cancer, hypothyroidism, lupus erythematosus, AIDS,

 

 24   anemia, diabetes, and epilepsy.

 

 25             Chronic fatigue syndrome is another

 

                                                                51

 

  1   disorder that needs to be considered, but its

 

  2   symptoms are similar to major depression, but there

 

  3   tends to be more somatic symptoms, less mood,

 

  4   cognitive, and social symptoms.

 

  5             Medication-induced symptoms involve those

 

  6   induced by stimulants, neuroleptics, cortical

 

  7   steroids, and contraceptives.

 

  8             [Slide.]

 

  9             Bereavement is another issue that needs to

 

 10   be considered because there are a similarity of

 

 11   symptoms with major depressive disorder.  The

 

 12   diagnosis of major depression can be made if the

 

 13   bereaved child or adolescent has moderate or severe

 

 14   functional impairment, psychosis, suicidal thoughts

 

 15   or acts, and a prolonged course.

 

 16             Following bereavement, a predisposition to

 

 17   major depression may be related to prior major

 

 18   depression or a  family history of major depressive

 

 19   disorder.  In general, uncomplicated bereavement

 

 20   often remits in 6 to 12 months after a death.

 

 21             [Slide.]

 

 22             I would like to focus now on some issues

 

 23   of clinical course for major depressive disorder.

 

 24   The median duration for clinically referred

 

 25   children and adolescents tends to be 7 to 9 months,

 

                                                                52

 

  1   and in community samples it has been reported to be

 

  2   shorter, approximately 1 to 2 months.

 

  3             Predictors of a longer course or duration

 

  4   involve the severity of depression, the degree of

 

  5   comorbidity, the presence of negative life events,

 

  6   parental psychiatric disorders, and poor social

 

  7   functioning.

 

  8             Remission of major depression is defined

 

  9   as a period of 2 weeks to 2 months in which there

 

 10   is one clinically significant symptom only.  Ninety

 

 11   percent of children and adolescents with major

 

 12   depression remit in 1 to 2 years after the onset of

 

 13   the major depressive episode.

 

 14             [Slide.]

 

 15             Approximately 6 to 10 percent of those

 

 16   with major depression have a protracted course.  A

 

 17   relapse is an episode of major depression during

 

 18   the period of remission, and predictors of relapse

 

 19   include the natural course of major depression,

 

 20   namely, the nature of the way it manifests, lack of

 

 21   compliance with interventions, negative life

 

 22   events, rapid decrease, or discontinuation of

 

 23   therapy.

 

 24             Forty to 60 percent of youth with major

 

 25   depression tend to have a relapse after successful

 

                                                                53

 

  1   acute therapy, it's a high rate.  This indicates

 

  2   the need for continuous treatment.

 

  3             [Slide.]

 

  4             Recurrences occur also, and this is an

 

  5   emergence of major depressive symptoms during a

 

  6   period of recovery, which is an asymptomatic period

 

  7   of more than two months. Clinical and non-clinical

 

  8   samples have a probability of recurrence of

 

  9   approximately 20 to 60 percent within one or two

 

 10   years after recovery, and 70 percent after five

 

 11   years of recovery.  So, this is a chronic disorder.

 

 12             Predictors of recurrence include the

 

 13   earlier age of onset of major depressive symptoms,

 

 14   increased number of prior episodes of major

 

 15   depression, the severity of an initial episode, the

 

 16   presence of psychosis, the degree of psychosocial

 

 17   stressors, the presence of dysthymia and other

 

 18   comorbidities, and the lack of compliance with

 

 19   therapy.

 

 20             [Slide.]

 

 21             In terms of the clinical course, children

 

 22   with major depression, 20 to 40 percent develop

 

 23   bipolar disorder in 5 years after the onset of

 

 24   major depressive disorder, and predictors for the

 

 25   bipolar disorder onset would be early onset of

 

                                                                54

 

  1   major depression, the presence of psychomotor

 

  2   retardation, psychosis, a family history of

 

  3   psychotic depression, a heavy family loading for

 

  4   mood disorders, and psychopharmacologically-induced

 

  5   hypomania.

 

  6             [Slide.]

 

  7             Other factors that affect the clinical

 

  8   course of major depression is that the risk for

 

  9   depression increases 2- to 4-fold after puberty, a

 

 10   very important developmental issue, and that

 

 11   various genetic, as well as environmental, factors

 

 12   influence the pathogenesis of major depression.

 

 13             For example, shared family environmental

 

 14   or not extra-environmental non-shared issues tend

 

 15   to be very important in affecting the course, as

 

 16   well as those youngsters who have high genetic risk

 

 17   are more sensitive to  various environmental

 

 18   stressors.

 

 19             Children with depressed parents are three

 

 20   times more likely to have a lifetime episode of a

 

 21   major depressive disorder.

 

 22             [Slide.]

 

 23             The prevalence of children's first-degree

 

 24   relatives when children have major depression tends

 

 25   to be 30 to 50 percent.  In addition, parents also

 

                                                                55

 

  1   may have major depression and anxiety disorders,

 

  2   substance abuse, as well  as personality disorders.

 

  3             [Slide.]

 

  4             The clinical course of children with major

 

  5   depression is also associated with poor school

 

  6   success, low parental satisfaction with the child,

 

  7   a very important parent-child problem, learning

 

  8   problems, other psychiatric disorders that

 

  9   interfere with the child's learning.

 

 10             The course may also be affected by various

 

 11   personality traits, such as the child being

 

 12   judgmental, having angry outbursts frequently, poor

 

 13   self-esteem, and dependency.  Cognitive styles and

 

 14   temperament, such as negative attributional styles,

 

 15   may affect the course of major depressive disorder.

 

 16             Early adverse experiences, such as

 

 17   parental separation or death, may affect the

 

 18   course.  Recent adverse events may affect the

 

 19   course, family conflicts, neglect, and abuse,

 

 20   biological factors, such as inability to regulate

 

 21   emotions, and/or distress.

 

 22             [Slide.]

 

 23             The relation of dysthymia in major

 

 24   depression is quite important because dysthymia is

 

 25   associated with an increased risk for major

 

                                                                56

 

  1   depressive disorder.  Seventy percent of youth with

 

  2   dysthymia tend to have major depressive disorders.

 

  3             Dysthymia has a mean episode of

 

  4   approximately 3  to 4 years for both clinical and

 

  5   non-clinical in community samples.  A first major

 

  6   depressive episode usually occurs 2 to 3 years

 

  7   after the onset of dysthymia, which may be

 

  8   considered a gateway to the developing recurrent

 

  9   major depressive disorder.

 

 10             The risk for dysthymia is associated with

 

 11   chaotic families, high family loading for mood

 

 12   disorders particularly dysthymia.

 

 13             [Slide.]

 

 14             Another important issue in terms of course

 

 15   of children with major depression is that they are

 

 16   at very high risk for suicidal tendencies.  There

 

 17   are a few studies, some of which I will highlight,

 

 18   one by Marika Kovacs, which is a 9-year follow-up

 

 19   of prepubertal children.  She had various groups

 

 20   that she studied.

 

 21             At the time of follow-up, children who had

 

 22   major depression had a 74 percent rate of suicidal

 

 23   thinking and a 28 percent rate of suicide attempts.

 

 24   Those who initially had dysthymia, also had a 78

 

 25   percent rate of suicidal thinking, and close to 20

 

                                                                57

 

  1   percent rate of suicide attempts.

 

  2             Compared to children with adjustment

 

  3   disorder or other types of psychiatric disorders

 

  4   that are not mood disorders, these rates for

 

  5   children with mood disorders, namely, major

 

  6   depression and dysthymia, are significantly greater

 

  7   for suicidal thinking and suicidal attempts.

 

  8             Our own follow-up study of 6 to 8 years

 

  9   for prepubertal inpatients indicated that there is

 

 10   a 5 times risk for suicide attempt when the

 

 11   prepubertal children reach adolescence if they had

 

 12   a prepubertal mood disorder.

 

 13             [Slide.]

 

 14             A community sample study indicated that

 

 15   the 1-year incidence of suicide attempts in

 

 16   adolescence was associated with a 12 to 15 times

 

 17   greater risk if the youngster had major depressive

 

 18   disorder.

 

 19             [Slide.]

 

 20             There are various concerns about treating

 

 21   major depressive disorder.  The treatment research,

 

 22   first of all, is relatively sparse in children and

 

 23   adolescents.  There are varied opinions about

 

 24   whether psychotherapy or pharmacotherapy, or a

 

 25   combination should be the first-line treatment.

 

                                                                58

 

  1             The initial acute treatment often depends

 

  2   on the severity of symptoms of major depression,

 

  3   the number of prior episodes, the chronicity, the

 

  4   age, contextual issues in the family, school, and

 

  5   other environmental features, the degree of

 

  6   negative life events, the compliance with

 

  7   treatment, prior treatment responses, and the

 

  8   motivation for treatment.

 

  9             [Slide.]

 

 10             Some general principles that clinicians

 

 11   have thought about is that psychotherapy may be

 

 12   considered for the more mild or moderate major

 

 13   depressive symptoms.  Empirical effect of

 

 14   psychotherapies that we now know of include

 

 15   cognitive behavioral therapy and ITP, interpersonal

 

 16   psychotherapy.

 

 17             Antidepressants may be used for youngsters

 

 18   who have symptoms of major depressive disorder,

 

 19   nonrapid cycling by polar states, psychotic

 

 20   depression, depression with severe symptoms that

 

 21   prevent effective psychotherapy or that fail to

 

 22   respond to psychotherapy.

 

 23             Also, due to the psychosocial context,

 

 24   frequently pharmacotherapy alone may not be

 

 25   effective.

 

                                                                59

 

  1             [Slide.]

 

  2             The treatment of children with major

 

  3   depression, there are very few studies of acute

 

  4   treatment using medication.  There are few

 

  5   pharmacokinetic or dose-range studies with children

 

  6   and adolescents.

 

  7             The SSRIs are thought to perhaps induce

 

  8   mania, hypomania, behavioral activation, which

 

  9   might include impulsive behavior, silly or agitated

 

 10   daring, and there are no long-term studies for the

 

 11   treatment of major depression.

 

 12             I am going to actually conclude, and not

 

 13   go over some of these studies, which you will hear

 

 14   about I am sure today, and to say again that major

 

 15   depressive disorder in children and adolescents is

 

 16   complex and heterogeneous regarding its clinical

 

 17   course, comorbidities, predictors, of course, need

 

 18   for specificity of treatment, and the developmental

 

 19   variations.

 

 20             It is a chronic condition that recurs with

 

 21   serious morbidity including suicidal tendencies.

 

 22   There are few treatment studies, which limit our

 

 23   knowledge of the methods to reduce these symptoms

 

 24   and the morbidities.

 

 25             There is a need to clarify the indications

 

                                                                60

 

  1   for pharmacotherapy, as well as psychotherapy

 

  2   whether alone or used in combination, as well as

 

  3   that to maintain youngsters who have already

 

  4   exhibited major depressive disorder.

 

  5             Thank you.

 

  6             DR. RUDORFER:  Thank you, Dr. Pfeffer.

 

  7             We will now turn to Dr. David Shaffer of

 

  8   Columbia University who will speak on the topic of

 

  9   Suicide and Related Problems in Adolescents.

 

 10           Suicide and Related Problems in Adolescents

 

 11             DR. SHAFFER:  Good morning.

 

 12             [Slide.]

 

 13             I am going to review the epidemiology of

 

 14   youth suicide and also some of its phenomenology as

 

 15   it may be relevant to the discussion that you are

 

 16   going to be having for the rest of the day.  It is

 

 17   a topic that I have been involved in for a number

 

 18   of years, and I hope that it is helpful.

 

 19             [Slide.]

 

 20             In the United States, in 2001, the last

 

 21   year for which we have statistics of this kind,

 

 22   about 1,600 15- to 19-year-olds committed suicide.

 

 23   You will see that that is the third leading cause

 

 24   of death in the United States, and in most

 

 25   countries, it is the second leading cause of death,

 

                                                                61

 

  1   but in the United States and a few other countries,

 

  2   homicide comes between that.

 

  3             You can also see that suicide accounted

 

  4   for more deaths, over twice as many deaths as from

 

  5   cancer, in fact, more deaths than all of the other

 

  6   major physical conditions combined.

 

  7             [Slide.]

 

  8             The methods by which children commit

 

  9   suicide are, by and large, very similar to those --

 

 10   with children, young people -- are very similar to

 

 11   those which are used by adults.  The main

 

 12   difference is that hanging is somewhat more common

 

 13   in young people, and the figures that I have got

 

 14   here on the left are the 5- to 19-year-olds, on the

 

 15   right, over the rest of the population.

 

 16             You will see a few other things of

 

 17   interest.  Ingestion is primarily a cause of death

 

 18   in females, firearms  are more common in males than

 

 19   in females, and carbon monoxide poisoning is one of

 

 20   the few conditions where there have been any

 

 21   changes in causes of death, so that the proportion

 

 22   of suicides attributable to carbon monoxide

 

 23   poisoning has declined since the introduction of

 

 24   catalytic converters.  The proportion of suicides

 

 25   attributable to firearms, even though there has

 

                                                                62

 

  1   been a general decline in access and use of

 

  2   firearms, has not declined.

 

  3             You can also see from this slide that

 

  4   cutting, which there is often a lot of debate about

 

  5   cutting, whether that is or is not a form of

 

  6   suicide, in fact, accounts for a very negligible

 

  7   number of deaths.  I think most people would view

 

  8   cutting as not being part of the suicide syndrome.

 

  9             [Slide.]

 

 10             This is a chart which shows the

 

 11   distribution of suicide by different genders and

 

 12   ethnic groups across the life cycle, and the top

 

 13   line represents white males.  That is followed by

 

 14   African-American males, then white females and

 

 15   black females.  Where the vertical arrow is, is the

 

 16   rate for adolescents.

 

 17             You can see several things from this

 

 18   chart.  First of all, I should say that this chart

 

 19   is remarkably similar in one country to another, so

 

 20   there is something about this pattern of mortality

 

 21   which seems to be almost independent of cultural

 

 22   influence.

 

 23             You do get very big differences in parts

 

 24   of Asia, but apart from that, it is remarkably

 

 25   similar.  That is to say that there are very, very

 

                                                                63

 

  1   few suicides that occur before puberty, that

 

  2   adolescents occupies an intermediate position

 

  3   between childhood and adulthood, and then one gets

 

  4   this very striking increase in the rate in elderly

 

  5   males and relatively little variation by age in

 

  6   females.

 

  7             [Slide.]

 

  8             If we deconstruct this a little more and

 

  9   thus look at adolescents, what you can see is that

 

 10   here, most 10- to 15-year-old suicides actually are

 

 11   occurring amongst 14- and 15-year-olds, and that

 

 12   suicide before puberty is very, very rare.

 

 13             Sometimes you will read about big

 

 14   increases or big changes in the young child rate,

 

 15   but the rates are very low and very unstable as a

 

 16   result of that, and I don't think that one can draw

 

 17   very many conclusions about suicide before puberty.

 

 18             That may also be relevant to the matters

 

 19   that you are considering today, because both

 

 20   suicide and depression are relatively uncommon,

 

 21   very uncommon before puberty, and that may mean

 

 22   that what we should be looking at is what are the

 

 23   differences between adolescents and adults.

 

 24             [Slide.]

 

 25             The United States ranks around about in

 

                                                                64

 

  1   the bottom of the top tier of rates in the world.

 

  2   Most countries with the highest rates of suicide

 

  3   are in Northern/Eastern Europe, but the United

 

  4   States is 16th as far as males are concerned, and

 

  5   ranks 22nd as far as females.

 

  6             There are quite big differences in gender

 

  7   mainly in China, where suicide is the 7th country

 

  8   for female deaths, but much lower for male deaths,

 

  9   but, in general, the United States is not

 

 10   distinguished by having a particularly high or a

 

 11   particularly low rate.

 

 12             [Slide.]

 

 13             We know quite a lot about the frequency of

 

 14   suicidal ideation and attempts from large community

 

 15   studies, particularly the Youth Risk Behavior

 

 16   Study, which is a study that is carried out by the

 

 17   National Center for Health Statistics every two

 

 18   years, for which different states volunteer, and a

 

 19   broad population of between 15- and 20,000 high

 

 20   school students are interviewed using self-report

 

 21   measures every two years.

 

 22             [Slide.]

 

 23             What one has been able to see from that

 

 24   really was a big eye-opener.  That is to say, that

 

 25   suicidal ideation in high school students is

 

                                                                65

 

  1   extraordinarily common.  Almost 20 percent of

 

  2   American high school students will think about

 

  3   suicide during the past year.

 

  4             Suicide attempts are also very common, so

 

  5   that the overall rate is about 9 percent, and if

 

  6   you track these YRBS results, they don't show an

 

  7   awful lot of variation from one year to another.

 

  8             I have highlighted by color the difference

 

  9   between the self-reported attempts and attempts

 

 10   that received medical attention, because only about

 

 11   a quarter of attempts do receive medical attention

 

 12   or are brought to medical attention.

 

 13             I think what is important about this is

 

 14   that adolescents may not disclose even suicidal

 

 15   attempt behavior, let alone suicide ideation, and

 

 16   that is frequently not known to either their

 

 17   parents or to others, and that also has to be a

 

 18   consideration, I think, in what you are

 

 19   considering.

 

 20             Both ideation and attempts, and attempts

 

 21   which receive medical attention, are far, far more

 

 22   common than completed suicide, and if you were to

 

 23   array these out by gender, we estimate that there

 

 24   are about 4,000 suicide attempts for every female

 

 25   suicide death, but about 400 male attempts for

 

                                                                66

 

  1   every male death, so that you do get these big

 

  2   gender discrepancies with attempts being more

 

  3   common in females and deaths being more common in

 

  4   males, but you can see that the ratio of attempts

 

  5   to deaths is extreme particularly in females.

 

  6             [Slide.]

 

  7             Not only do many adolescents attempt and

 

  8   think about suicide, but they do it quite often, so

 

  9   that from the studies that we have, about half of

 

 10   suicide attempters will  make only one attempt a

 

 11   year, and nearly a half will make two or more, in

 

 12   many instances, four or more deaths per year.

 

 13             We get similar findings in clinical or

 

 14   community studies, and we do know from follow-up

 

 15   studies that having made one attempt will increase

 

 16   the probability of another 15-fold, so that can be

 

 17   quite an important consideration if you are

 

 18   planning a medication study or any other kind of

 

 19   therapeutic study, because maybe what you need to

 

 20   find out about is not so much the state of

 

 21   suicidality at the time of inception into the

 

 22   study, but the history of suicidality as well

 

 23   because that could be an important factor in either

 

 24   stratifying for suicide risk or for filtering it

 

 25   out or filtering it in.

 

                                                                67

 

  1             The episodes of ideation, again, you can

 

  2   see that most youngsters who think about suicide do

 

  3   so more than once a year, and in many instances, it

 

  4   is several times a year.

 

  5             [Slide.]

 

  6             With respect to how suicidal adolescents

 

  7   are excluded from psychopharm studies, because in

 

  8   general, the studies of depression have excluded

 

  9   suicidal instances, there have been variations in

 

 10   the techniques that have been used, there has been

 

 11   no uniform approach, and that may be a

 

 12   consideration that the committee would want to look

 

 13   at in weighing up different studies and trying to

 

 14   compare them.

 

 15             [Slide.]

 

 16             Finally, with epidemiology, I just want to

 

 17   show you how the suicide rate has changed over the

 

 18   last century. This is the 20th century youth

 

 19   suicide profile.

 

 20             What you can see is that starting I guess

 

 21   in the late '50s, the top line are males and the

 

 22   bottom are females, the male youth suicide rate

 

 23   started to increase, and it increased and increased

 

 24   3-fold, finally, reaching some sort of asymptote

 

 25   around in the late '80s, peaked a little bit more

 

                                                                68

 

  1   towards the end, and then started to decline.

 

  2             So, starting in 1994, we have had an

 

  3   extraordinary decline in the youth suicide rate,

 

  4   which is very interesting.  It has been parallel

 

  5   twice before, once coinciding with World War I and

 

  6   once with World War II.  We don't know what this

 

  7   could be due to, and that will be something that I

 

  8   am going to return to in a second or two.

 

  9             [Slide.]

 

 10             As far as the causes of suicide, far and

 

 11   away the most common finding in psychological

 

 12   autopsy studies, which interview friends and family

 

 13   after a death has taken place, are the very high

 

 14   rates of diagnosable psychiatric illness that are

 

 15   present, and in studies done in a variety of

 

 16   locations, 90 percent of completed suicides were

 

 17   diagnosable with a DSM diagnosis prior to their

 

 18   death, and the rates are  extraordinarily similar

 

 19   from location to location.

 

 20             [Slide.]

 

 21             The most common diagnoses are depression,

 

 22   antisocial behavior, substance abuse, and some form

 

 23   of anxiety, and most teen suicides occur in 16- to

 

 24   19-year-olds, and in that group, in 16- to

 

 25   19-year-old male suicides, it is important to know

 

                                                                69

 

  1   that two-thirds meet the criteria for substance or

 

  2   alcohol abuse.

 

  3             So, the occurrence of completed suicide is

 

  4   very closely linked to the occurrence of

 

  5   particularly alcohol abuse.

 

  6             [Slide.]

 

  7             As Cynthia Pfeffer outlined, and I won't

 

  8   repeat this, suicidality is extraordinarily common

 

  9   in depressed children and teens, both at the time

 

 10   of diagnosis -- and this is a meta-analysis from

 

 11   six studies -- ideation was present in about 60

 

 12   percent, a previous attempt in 30 percent, and

 

 13   during the follow-up period, attempts also occurred

 

 14   frequently, so that when you find ideation and

 

 15   attempts during the course of treatment of

 

 16   depression, as I say, this is a well-reported

 

 17   phenomenon.

 

 18             [Slide.]

 

 19             There are other factors that predispose to

 

 20   suicide.  Imitation is one that is particularly

 

 21   worrying because it means that public information

 

 22   campaigns may have a double-edged sword, because we

 

 23   do know that you do get suicide epidemics in the

 

 24   young.

 

 25             There is a contagion factor, and the

 

                                                                70

 

  1   Centers for Disease Control are very actively

 

  2   engaged in trying to find ways of reducing this,

 

  3   and there are now a host of studies in adults, but

 

  4   not yet in children or adolescents, that show that

 

  5   biological abnormalities may predispose to

 

  6   impulsive responses to stress and a family history

 

  7   of suicide.

 

  8             [Slide.]

 

  9             We can devise a schema, which you have got

 

 10   in your handout, which can show the route from any

 

 11   of these disorders to suicide ideation and from

 

 12   there to suicide, but  I don't think that there is

 

 13   time to get into that model in this presentation.

 

 14             [Slide.]

 

 15             I just want to go back to changing rates,

 

 16   because they may be very relevant to today's

 

 17   discussion.

 

 18             [Slide.]

 

 19             As I showed you, there has been this very

 

 20   striking and encouraging reduction in male suicide

 

 21   males amongst young males 15 to 24.  It is even

 

 22   more striking actually if you look at 15- to

 

 23   19-year-olds.

 

 24             What is important is that this has not

 

 25   been a United States phenomenon only.  It has been

 

                                                                71

 

  1   reported in a large number of other industrialized

 

  2   nations.

 

  3             In the list that I have given here, three

 

  4   nations, Austria, Germany, and Switzerland, have

 

  5   been experiencing a decline which well predated the

 

  6   introduction of any of the newer groups of

 

  7   antidepressants, but in all of the other countries,

 

  8   the decline started sometime after 1988.

 

  9             There is only one country which seems to

 

 10   have a stable or rising rate, which is Scotland,

 

 11   and there are a number of possible reasons that

 

 12   have been debated to explain these reductions.

 

 13             One is that during the '90s, at least in

 

 14   the United States, there was economic prosperity, a

 

 15   decline in unemployment, and other social indices

 

 16   tended to improve, but rates also started to

 

 17   decline in high youth unemployment countries in

 

 18   Europe, and the relationship between SES and

 

 19   suicide is not strong, and, in fact, it hasn't

 

 20   really been established.

 

 21             The first thought was if so many suicides

 

 22   are associated with drug and alcohol abuse, maybe

 

 23   exposure to drugs and alcohol would have been

 

 24   reduced during this time, and this is certainly my

 

 25   first guess.  However, use and abuse rates have not

 

                                                                72

 

  1   changed, if anything, they have continued to inch

 

  2   up.

 

  3             [Slide.]

 

  4             Reduced firearm availability, the Brady

 

  5   Act was introduced in 1994, and there is evidence

 

  6   from tracking studies that ownership and use of

 

  7   firearms started to decline around about 1980, but

 

  8   the proportion of suicides by firearm has gone

 

  9   unchanged, and although there have been very

 

 10   striking declines in accidents attributable to

 

 11   firearms, it is not clear that we can point to the

 

 12   reduction in suicides as being caused by that.

 

 13             Also, the declines have been noted in

 

 14   countries in which there are almost no firearm

 

 15   suicides, so this doesn't seem to be a very

 

 16   plausible explanation.

 

 17             [Slide.]

 

 18             More psychotherapeutic treatment is a

 

 19   possibility, but, in fact, the data seem to suggest

 

 20   that visits for psychotherapy have declined

 

 21   consistently over the past 10 to 12 years, more

 

 22   psychopharmacologic treatment, and you will have

 

 23   heard that there has been an enormous increase in

 

 24   exposure to antidepressants during this period in

 

 25   many countries, or it could be a nonspecific

 

                                                                73

 

  1   finding, a better recognition of adolescent suicide

 

  2   with some nonspecific interventions or some

 

  3   combination of the above.

 

  4             [Slide.]

 

  5             A word or two about treatment.  There have

 

  6   been some useful Cochrane analyses looking at

 

  7   effective treatments for suicide attempts.  These

 

  8   have mainly been done in adults, and only two

 

  9   treatments emerged as being successful.

 

 10             One is dialectical behavior therapy, which

 

 11   is a  very specific form of therapy which is hard

 

 12   to come by because very few people are trained in

 

 13   it, and one study looking at flupenthixol, which is

 

 14   an antipsychotic or neuroleptic, in multiple

 

 15   attempters.

 

 16             There have also been studies showing

 

 17   lithium or at least discontinuation of lithium

 

 18   results in an increase in the suicidality, and

 

 19   Clozaril seems to have a specific suicide sparing

 

 20   effect in schizophrenia.

 

 21             But apart from that, we don't have much to

 

 22   guide us, and there is nothing out there which

 

 23   tells the clinician what to do with this very

 

 24   common problem.

 

 25             [Slide.]

 

                                                                74

 

  1             Maybe that is why, but, in general, teens

 

  2   who do commit suicide tend to be relatively

 

  3   undertreated compared to adults, so that, for

 

  4   example, the top three lines show that between 30

 

  5   and 60 percent of adults who commit suicide will

 

  6   have had mental health treatment, but in

 

  7   adolescents, very few have had that, so it is

 

  8   getting between 7 and 21 percent, they are an

 

  9   undertreated group.

 

 10             [Slide.]

 

 11             Furthermore, one of the things that has

 

 12   been interesting to epidemiologists over this

 

 13   current debate is do you find antidepressants in

 

 14   toxicologic studies of completed suicides, and Exen

 

 15   [ph] in Sweden has done a study showing that the

 

 16   findings in autopsy studies suggest that suicides

 

 17   are significantly undertreated with SSRIs compared

 

 18   to the rest of the population.

 

 19             There has only been one study in youth,

 

 20   and that is from the Utah Youth Suicide Study by

 

 21   Dr. Gray, and he has looked at 50 psychological

 

 22   autopsies, all of whom had careful toxicology

 

 23   investigations.

 

 24             A quarter of those had been prescribed

 

 25   antidepressants, but in none of those cases were

 

                                                                75

 

  1   antidepressants found at autopsy, so we know that

 

  2   teenagers often don't take their medication, and

 

  3   certainly they didn't seem to be taking it in this

 

  4   case.

 

  5             [Slide.]

 

  6             So, I would just like to conclude with

 

  7   some cautions and considerations.  Ideation and

 

  8   attempts are very common in depressed teens, and

 

  9   they recur frequently, so finding them in

 

 10   youngsters being treated for depression is, of

 

 11   course, not surprising.   That doesn't address any

 

 12   treatment effect that might be found.

 

 13             A methodological point.  Teenagers often

 

 14   conceal ideation and attempts unless they are asked

 

 15   about them directly.  Self-report facilitates

 

 16   disclosure.  It is my understanding that we are

 

 17   heavily dependent upon event reports in these data,

 

 18   and event reports may be influenced by the mode of

 

 19   elicitation.

 

 20             They are not used with a glossary which

 

 21   precisely defines how things should be classified,

 

 22   so misclassifications can occur.

 

 23             Self-harm is a term that is used by some,

 

 24   but not others in the mental health profession.  It

 

 25   is a very heterogeneous descriptor and not all

 

                                                                76

 

  1   types of self-harm are associated with suicidal

 

  2   intent.

 

  3             There have been no direct studies with

 

  4   frequent and careful measurement examining whether

 

  5   SSRIs increase, decrease, or have no effect on

 

  6   suicidal ideation and behavior, so that we are

 

  7   dependent very much on inference, but maybe that is

 

  8   always the case.

 

  9             I just would like to conclude with the

 

 10   following. After increasing for 35 years, teen

 

 11   suicide rates have been declining consistently in

 

 12   many countries.  During this period, there has been

 

 13   a marked increase in exposure of teens to SSRI

 

 14   antidepressants.

 

 15             These trends could be related.  This is

 

 16   ecologic, and we don't know whether they are

 

 17   related, but at the moment we don't have a better

 

 18   explanation for the turnabout of a condition that

 

 19   led to the death of tens of thousands of young

 

 20   people.

 

 21             I would like to stop at that point.

 

 22             DR. RUDORFER:  Thank you very much.

 

 23             At this time, just before our break, I

 

 24   have one announcement to make.  Any open public

 

 25   hearing speakers who have not yet signed in, please

 

                                                                77

 

  1   do so immediately.  We will only be able to call

 

  2   upon speakers who have formally signed in, so we

 

  3   wouldn't want you to miss your chance.

 

  4             We have time for a 15-second break, but I

 

  5   am told that may not work, so why don't we take 5

 

  6   minutes or as close to that as we can work, and we

 

  7   will come back for our open public hearing.

 

  8   Thanks.

 

  9             [Break.]

 

 10                       Open Public Hearing

 

 11             DR. RUDORFER:  There is specific guidance

 

 12   from the FDA that I would like to read.  This

 

 13   applies to all meetings or considered general

 

 14   matters meetings, and as we heard earlier from

 

 15   Anuja, since we are not focusing on one specific

 

 16   product here, that encompasses this joint meeting.

 

 17             Both the Food and Drug Administration, or

 

 18   FDA, and the public believe in a transparent

 

 19   process for information gathering and

 

 20   decisionmaking.  To ensure such transparency at the

 

 21   open public hearing sessions of the Advisory

 

 22   Committee meeting, FDA believes that it is

 

 23   important to understand the context of an

 

 24   individual's presentation.

 

 25             For this reason -- and I am addressing the

 

                                                                78

 

  1   speakers this morning -- FDA encourages you, the

 

  2   open public hearing speaker, at the beginning of

 

  3   your oral statement to advise the committee of any

 

  4   financial relationship you may have with any

 

  5   company or any group that is likely to be impacted

 

  6   by the topic of this meeting.  For example, the

 

  7   financial information may include a company's or a

 

  8   group's payment of your travel, lodging, or other

 

  9   expenses in connection with your attendance at the

 

 10   meeting.

 

 11             Likewise, FDA encourages you at the

 

 12   beginning of your statement to advise the committee

 

 13   if you do not have any such financial

 

 14   relationships.  If you choose not to address the

 

 15   issue of financial relationships at the beginning

 

 16   of your statement, it will not preclude you from

 

 17   speaking.

 

 18             As I mentioned earlier, the clock dictates

 

 19   only a limited amount of time for each speaker.  I

 

 20   would like to run all night, but I hear an ice

 

 21   storm is coming, so in the interest of time, we

 

 22   have a light warning system, and each speaker,

 

 23   please be advised, when you see the yellow light,

 

 24   you have 30 seconds remaining, so please start to

 

 25   wrap up.

 

                                                                79

 

  1             The flashing red light means you are out

 

  2   of time and the microphone will go off.  I have

 

  3   asked them to let you finish your sentence for

 

  4   three or four words, but it is out of our hands.

 

  5             We have two speaker-ready chairs, so I am

 

  6   asked to remind you that when your two away from

 

  7   your number, please be sure you are in one of

 

  8   those.

 

  9             Speakers are assigned by number and we

 

 10   will begin with Number 1.

 

 11                Irving Kirsch and David Antonuccio

 

 12             DR. KIRSCH:  My name is Irving Kirsch.

 

 13   Baum, Hedlund has paid for my air tickets.  I

 

 14   decided to come before knowing that.

 

 15             Dr. David Antonuccio, Amanda Drews, and I

 

 16   are reviewing the published literature evaluating

 

 17   the efficacy of antidepressants in depressed

 

 18   children.  A total of 12 randomized, controlled

 

 19   clinical trials have been published.

 

 20             Two-thirds of these trials failed to find

 

 21   any significant benefit of medication over inert

 

 22   placebo.  Only 4 trials reported significant

 

 23   differences, and these did so only on

 

 24   clinician-rated measures, not on patient-rated

 

 25   measures.

 

                                                                80

 

  1             When the data from these trials are

 

  2   combined, the placebo response is found to be 87

 

  3   percent of the drug response.  This means that the

 

  4   drug effect is only 13 percent of the drug

 

  5   response.  This is not a clinically significant

 

  6   effect.

 

  7             Many children get better when given

 

  8   antidepressants, but the data indicate that this is

 

  9   largely a placebo effect.  These conclusions are

 

 10   consistent with those found in 7 previous published

 

 11   reviews.

 

 12             To summarize, the published clinical trial

 

 13   data show that the therapeutic benefits of

 

 14   antidepressants for children is negligible at best.

 

 15             David.

 

 16             DR. ANTONUCCIO:  These results were drawn

 

 17   from studies with design flaws that typically favor

 

 18   the study drug.  For example, they frequently

 

 19   exclude placebo responders before random

 

 20   assignment, rely on ratings by clinicians who have

 

 21   a vested interest in the outcome, and are likely to

 

 22   be unblinded by medication side effects.

 

 23             Furthermore, these results are drawn from

 

 24   the published literature which is subject to

 

 25   publication bias and file drawer problems meaning

 

                                                                81

 

  1   that many studies with negative results do not get

 

  2   published.  Adding unpublished studies, most of

 

  3   which have negative results, will surely shrink the

 

  4   difference between antidepressants and placebo even

 

  5   further.

 

  6             In order to evaluate the cost

 

  7   effectiveness of antidepressant use in children,

 

  8   the committee must consider the benefits, as well

 

  9   as the risks.  Clinically meaningful benefits have

 

 10   not been adequately demonstrated in depressed

 

 11   children, therefore, no extra risk is warranted.

 

 12             An increased risk of suicidal behavior is

 

 13   certainly not justified by these minimal benefits.

 

 14   Neither are the established increased risks of

 

 15   other commonly reported side effects, which include

 

 16   agitation, insomnia, and gastrointestinal problems.

 

 17             The highest possible standard should be

 

 18   applied to scientific data involving drug treatment

 

 19   of children, because children are essentially

 

 20   involuntary patients.  Those of you on the

 

 21   committee who are parents know this to be true

 

 22   because when your children have prescription

 

 23   medication for something that ails them, you make

 

 24   them take it as prescribed whether they want to or

 

 25   not.

 

                                                                82

 

  1             Children given antidepressant medication

 

  2   often do get better, but so do children given

 

  3   placebo.  Thus, the clinical data suggest the

 

  4   improvement is due primarily, if not entirely, with

 

  5   placebo effect.

 

  6             Please be careful to ensure that our

 

  7   children are not exposed to risk without

 

  8   commensurate benefit.

 

  9             DR. RUDORFER:  Thank you.

 

 10             May we have the next speaker, Number 2.

 

 11                         Lisa Van Syckel

 

 12             MS. SYCKEL:  Good morning, ladies and

 

 13   gentlemen. My name is Lisa Van Syckel, and my

 

 14   daughter, Michelle, at the age of 15, was placed on

 

 15   Paxil.  She was diagnosed with depression and

 

 16   anorexia nervosa.  It turned out that that

 

 17   diagnosis was wrong, she actually had Lyme Disease.

 

 18             My daughter self-mutilated, became

 

 19   psychotic, became violent, attempted suicide twice.

 

 20   My daughter survived those two suicide attempts,

 

 21   not because of the drug, because of the police

 

 22   officers who were summoned to my home.

 

 23             Michelle has suffered severe withdrawal.

 

 24   She is constantly ill with flu-like symptoms.  She

 

 25   has had rectal bleeding, she has vomited blood. 

 

                                                                83

 

  1   She has had her friends at school call her

 

  2   "Psycho," all because she was misdiagnosed and all

 

  3   because everyone has withheld from the public the

 

  4   adverse effects of Paxil.

 

  5             I am a parent.  It is my right to make an

 

  6   informed decision on behalf of my daughter.  You

 

  7   did not allow me to make that informed decision and

 

  8   she was harmed.  We are blessed because Michelle

 

  9   did not die, and Michelle is now attending

 

 10   university and doing beautifully.

 

 11             Please, have respect for our children,

 

 12   make sure that you put proper warnings on these

 

 13   medications.  Our children's lives are at stake

 

 14   here, because not only does it cause suicide, it

 

 15   also causes them to become violent, very, very

 

 16   violent.

 

 17             Thank you.

 

 18             DR. RUDORFER:  Thank you.

 

 19             May we have the next speaker, Number 3.

 

 20                      Ann Blake Tracy, Ph.D.

 

 21             DR. TRACY:  I would like to say, first of

 

 22   all, that this is a meeting that should not be

 

 23   taking place today.  I testified at an FDA hearing

 

 24   similar to this in 1991, and these drugs should

 

 25   have been banned at that time in my opinion.

 

                                                                84

 

  1             I am Dr. Ann Blake Tracy, a Ph.D. in

 

  2   health sciences with emphasis on psychology.  I

 

  3   have spent the last 14 years researching the SSRIs

 

  4   and working with patients who are having adverse

 

  5   reactions to these medications.  I am also the

 

  6   author of Prozac: Panacea or Pandora, Our Serotonin

 

  7   Nightmare.

 

  8             I have testified in criminal and civil

 

  9   cases for 12 years concerning these medications,

 

 10   and I am greatly concerned about the use of these

 

 11   drugs among children, with developing brains, who

 

 12   have far more reactions than the general public

 

 13   would, as I am the elderly who are having severe

 

 14   adverse reactions.

 

 15             What I presented to the FDA in 1991, I

 

 16   would like to present again.  Each of you will get

 

 17   a copy of this.  This is a 31-year-old patient on

 

 18   Prozac for six months, shows the patient, although

 

 19   appearing alert and functioning, in a total

 

 20   anesthetic sleep state while dreaming.  I believe

 

 21   technically, you could call that a REM sleep

 

 22   behavior disorder.

 

 23             The research now shows, this many years

 

 24   later, that 86 percent of the cases being diagnosed

 

 25   with this REM sleep behavior disorder are patients

 

                                                                85

 

  1   on antidepressants, 80 percent of those on SSRI

 

  2   antidepressants.

 

  3             There are some very famous cases that I

 

  4   believe manifest that very clearly, and in

 

  5   representing those families today, I would give you

 

  6   Andrea Yates, who drowned her five children while

 

  7   taking Effexor and Remeron.

 

  8             DR. RUDORFER:  Thank you.  I am afraid we

 

  9   are out of time now.

 

 10             DR. RUDORFER:  Thank you.

 

 11             Number 4, please.

 

 12                           Tom Woodward

 

 13             MR. WOODWARD:  My name is Tom Woodward.

 

 14   My wife Kathy and I have been married for 19 years

 

 15   and until 6 months ago had 4 children.  Our oldest

 

 16   child, Julie, hung herself after 7 days on Zoloft,

 

 17   and she was only 17, was a cautious child, and had

 

 18   no history of self-harm or suicide, nor was there

 

 19   any history of depression or suicide in our family.

 

 20             The doctors we spoke with stressed that

 

 21   Zoloft was safe and had very few side effects.  The

 

 22   possibility of violence, self-harm, or suicidal

 

 23   acts was never raised.  The two and a half pages we

 

 24   received with the Zoloft never mentioned self-harm

 

 25   or suicide.

 

                                                                86

 

  1             Julie began experiencing akathisia almost

 

  2   immediately.  We now know from a blood test from

 

  3   the coroner's office that she was not metabolizing

 

  4   the drug.

 

  5             We are 100 percent convinced that Zoloft

 

  6   killed our daughter.  We are here because we

 

  7   believe the system we have in place is flawed.  It

 

  8   is clear that the FDA is a political entity and its

 

  9   leadership has protected the economic interests of

 

 10   the drug industry.  Under the Bush administration,

 

 11   the FDA has placed the interests of the drug

 

 12   industry over protecting the American public.

 

 13             Dr. McClellan understands how important

 

 14   political contributions are particularly since his

 

 15   mother has headed up the Republican fund-raising in

 

 16   Texas.  Eighty-six percent of the $14 million in

 

 17   political contributions given by drug companies has

 

 18   gone to the Bush administration Republican

 

 19   candidates - what did Pfizer, Eli Lilly, and

 

 20   GlaxoSmithKline Beecham buy?

 

 21             The FDA should be a jealous advocate in

 

 22   protecting the American people.  Those in

 

 23   leadership positions within the FDA must be beyond

 

 24   reproach.  FDA's chief counsel Daniel Troy has

 

 25   spent his career defending the drug industry. 

 

                                                                87

 

  1   Suppressing unfavorable data may be legal, but is

 

  2   it ethical?

 

  3             If the trials don't favor a drug, the

 

  4   public never hears of them.  Legal maneuverings

 

  5   have thrown out the scientific method.  The drug

 

  6   industry must be compelled to produce all of their

 

  7   findings and studies.  I also believe public

 

  8   funding of these trials is warranted.

 

  9             Our daughter, Julie, had been excited

 

 10   about college and scored 1,300 in her SATs several

 

 11   weeks before her death. Instead of picking out

 

 12   colleges with our daughter, my wife and I had to

 

 13   pick out a cemetery plot for her.

 

 14             Instead of looking forward to visiting

 

 15   Julie at school, we now visit her grave.  The loss

 

 16   we have experienced is horrific.  We don't want

 

 17   another innocent child or family to suffer this

 

 18   tragedy.

 

 19             DR. RUDORFER:  Thank you, Mr. Woodward.

 

 20             May we have the next speaker, please.

 

 21                           Mark  Miller

 

 22             MR. MILLER:  My wife Cheryl and I

 

 23   desperately hope that our story, along with others

 

 24   that you will hear today, and I so proud of the

 

 25   teens and the young adults who you will hear from

 

                                                                88

 

  1   today, that they have the courage to come forward

 

  2   and talk with you personally.  I wish our son

 

  3   could, he cannot.

 

  4             There is a serious problem with the way

 

  5   SSRI medications are being prescribed today and

 

  6   how, in many cases, they can directly cause

 

  7   violence and suicidal behavior in those we love and

 

  8   treasure the most, our children.

 

  9             You see, we lost our 13-year-old son,

 

 10   Matt, in the summer of 1997.  He died after a

 

 11   psychiatrist we did not know gave him three sample

 

 12   bottles of a pill we had never heard of, for a

 

 13   perceived illness that his doctor could only guess

 

 14   at.

 

 15             We were advised with great authority that

 

 16   Matt was suffering from a chemical imbalance that

 

 17   could be helped by a new, wonderful medication

 

 18   called Zoloft.  It was safe, effective, only two

 

 19   minor side effects were cautioned with us -

 

 20   insomnia, indigestion.

 

 21             Now, I don't know if Matt had a chemical

 

 22   imbalance.  I do know this.  We had moved into to a

 

 23   new neighborhood a year before, a new school

 

 24   setting, he was uneasy.  He didn't have the friends

 

 25   he had grown up with in our old neighborhood.  Yes,

 

                                                                89

 

  1   our son was unhappy.

 

  2             So, Matt's doctor, a man we know through

 

  3   court testimony to have been a well-paid spokesman

 

  4   for Pfizer, gave us Zoloft.  He said, "Take these

 

  5   for a week, call me back when you know how Matt is

 

  6   doing."

 

  7             Matt didn't have a week.  He became

 

  8   agitated on the pills.  He did not sleep.  He did

 

  9   not eat.  He could not sit still.  That night, a

 

 10   Sunday, before leaving on vacation, after taking

 

 11   his 7th Zoloft tablet, he took his own life.

 

 12             This is important for you to know.  Matt

 

 13   hung himself from a bedroom closet hook, barely

 

 14   higher than he was tall.  To commit this

 

 15   unthinkable act, something he had never attempted

 

 16   before, never threatened to any family member,

 

 17   never talked about, he was actually able to pull

 

 18   his legs up off the floor and hold himself that way

 

 19   until he lost consciousness and forced himself to

 

 20   leave us.

 

 21             Matt's autopsy showed the levels of

 

 22   sertraline in his blood were three times the

 

 23   therapeutic minimum levels.

 

 24             You have an obligation today, this panel,

 

 25   to prevent this tragic story from being repeated

 

                                                                90

 

  1   over and over and over again.  I hope you will do

 

  2   the right thing.

 

  3             DR. RUDORFER:  Thank you, Mr. Miller.

 

  4             If we could have the next speaker, please.

 

  5                     Corey and Jay Baadsgaard

 

  6             MR. COREY BAADSGAARD:  Good morning.  My

 

  7   name is Corey Baadsgaard.  Four years ago I was

 

  8   diagnosed with having social anxiety disorder, and

 

  9   my family practitioner doctor, he prescribed Paxil

 

 10   20 milligrams.

 

 11             After about 8 1/2 months, I started taking

 

 12   40 milligrams of Paxil because it was not working

 

 13   at 20 milligrams.  A few months after that, I went

 

 14   back.  The same problem, it wasn't working, and he

 

 15   suggested I start taking a new medication called

 

 16   Effexor.

 

 17             He abruptly discontinued the Paxil and put

 

 18   me immediately on Effexor at 75 milligrams, and I

 

 19   was supposed to work up to 300 milligrams over a

 

 20   3-week period.  The day that I took the 300

 

 21   milligrams, I didn't feel very well and I stayed

 

 22   home from school.

 

 23             I went back to sleep and that evening I

 

 24   woke up in a juvenile detention center.  Unaware of

 

 25   what I had actually done, I asked one of the

 

                                                                91

 

  1   members of the juvenile detention center, and I

 

  2   found out that I had taken my high-powered rifle

 

  3   that I use for hunting to my third period class,

 

  4   took 23 of my classmates hostage and 1 teacher

 

  5   hostage.

 

  6             I spent 14 months in jail, not really

 

  7   knowing why I had been there, not really

 

  8   remembering anything that I had done.

 

  9             This whole thing has changed my whole

 

 10   family, it changed me, myself.  We were forced to

 

 11   move.  I cannot even go back to the same town that

 

 12   I lived in, I have to stay at least 25 miles away

 

 13   from city limits.

 

 14             These drugs are ridiculous.  They should

 

 15   not be prescribed unless it's absolutely last

 

 16   resort.

 

 17             MR. JAY BAADSGAARD:  These drugs are hell.

 

 18   Look at what they have done to my son.

 

 19             DR. RUDORFER:  Thank you.

 

 20             May we have the next speaker, please.

 

 21                           Joyce Storey

 

 22             MS. STOREY:  My son, Brian Storey, was 17

 

 23   years old in 1997.  Our family doctor diagnosed him

 

 24   with severe  depression.  He took blood, checked

 

 25   for drugs or any medical condition.  He found

 

                                                                92

 

  1   neither.  He gave me 14 Zoloft pills and said come

 

  2   back in two weeks.  He never told me they had side

 

  3   effects and he even said if a person is drinking or

 

  4   doing drugs, that Zoloft works well with them.

 

  5             Five days later, my son killed a woman.

 

  6   When they arrested him, he was drug-tested.  They

 

  7   found no illegal drugs, he was only on Zoloft.

 

  8   During his trial, the kids that testified with him

 

  9   and against him said he did no drugs or alcohol.

 

 10             The psychiatrist that examined him was Dr.

 

 11   James Merkangis from Connecticut.  He is also a

 

 12   Doctor of Neurology and is on the faculty at Yale

 

 13   University.  He said Brian had a manic reaction to

 

 14   Zoloft.  He testified Brian told him it was like

 

 15   being in a dream.

 

 16             The news media called my son the

 

 17   All-American boy, and he was.  He is now serving

 

 18   life without parole.  Six months later, another boy

 

 19   at my son's high school, Jeff Franklin, 17 years

 

 20   old, on Prozac, took an ax to both his parents and

 

 21   three of his brothers and sisters.  Both of his

 

 22   parents died.  He is serving two life sentences.

 

 23             This is not a coincidence.  There is a

 

 24   common denominator, teenager, severely depressed,

 

 25   on an SSRI antidepressant.  What is scary is that

 

                                                                93

 

  1   you are only hearing from a few of us that this has

 

  2   happened to, and there are a lot more out there.

 

  3             I am praying you will look at these drugs

 

  4   very closely and, at the very least, take them out

 

  5   of the hands of pediatricians and GPs.  These

 

  6   doctors are not psychiatrists, and they do not have

 

  7   the knowledge and experience in treating mentally

 

  8   ill children.

 

  9             My son never had a chance.  There are 13

 

 10   million people on these drugs, 6 to 8 million are

 

 11   children.  The question is why are we handing these

 

 12   drugs out like candy, and the answer is $17 billion

 

 13   a year business.  It is always about money.  Please

 

 14   help before more families are destroyed.

 

 15             Thank you.

 

 16             DR. RUDORFER:  Thank you.

 

 17             Next speaker, please.

 

 18                           Jame Tierney

 

 19             MS. JAME TIERNEY:  Good morning.  My name

 

 20   is Jame Tierney.  I was 14 years old when I was

 

 21   prescribed 75 milligrams of Effexor for migraine

 

 22   headaches.  I took this for about a year.  At the

 

 23   time, the drug lost its effectiveness and my doctor

 

 24   doubled the dose.

 

 25             For the next 9 months, my life as I had

 

                                                                94

 

  1   known it was gone.  I thought daily about suicide

 

  2   and hurting myself. I felt void of normal emotions.

 

  3   I was so belligerent, agitated, and filled with

 

  4   hate - hate for my family, my friends, and most of

 

  5   all myself.  Rage consumed me.  I felt trapped.

 

  6             I said and did things I had never done

 

  7   before and never would do now.  I had little

 

  8   control and little inhibition.  It was as if I was

 

  9   watching a movie and some villain was destroying

 

 10   all the relationships around me.  I spent my time

 

 11   alone and viciously fighting with my parents. They

 

 12   would ask what was wrong and what had happened to

 

 13   me.  I could not answer them because I did not know

 

 14   or understand myself.  I was terrified.

 

 15             I thank God my parents knew that wasn't

 

 16   really me and continued to search for answers.

 

 17   They found the answer to my uncharacteristic

 

 18   behavior.  It was the Effexor that my neurologist

 

 19   had prescribed for my migraine headaches.  I was

 

 20   not, repeat not, prescribed this drug for

 

 21   depression.  I have had no history of depression

 

 22   prior to or after I was off the Effexor.  For me,

 

 23   this drug caused the very symptoms it's supposed to

 

 24   alleviate.

 

 25             Due to the severe withdrawal symptoms,

 

                                                                95

 

  1   Prozac was used to get me off Effexor.  It worked,

 

  2   but the same personality and behavior problems

 

  3   reemerged.  Effexor and Prozac affected me the same

 

  4   way.  I had never had these feelings before I took

 

  5   Effexor, I have never had these feelings since I

 

  6   stopped taking the Effexor and Prozac.

 

  7             Effexor took three years from me and I

 

  8   will never get them back.  The horror of what these

 

  9   drugs did to me is ineffable.  These drugs are

 

 10   destroying lives everywhere.

 

 11             I implore you to please protect the

 

 12   children from these drugs.

 

 13             DR. RUDORFER:  Thank you very much.

 

 14             If we can have speaker Number 9, please.

 

 15                   Donna Taylor and Mark Taylor

 

 16             MS. TAYLOR:  Hi.  My name is Donna Taylor.

 

 17   My son was shot at Columbine.  He took 7 to 13

 

 18   bullets though his chest and nearly died.  I also

 

 19   have other members of the family that have died

 

 20   since then on these drugs, but we can't get into

 

 21   that right now, and many, many people that we know,

 

 22   that families have been divided and separated, and

 

 23   there is just all kinds of divorces and all that

 

 24   going on from these drugs.

 

 25             I will let Mark speak.

 

                                                                96

 

  1             MR. TAYLOR:  First of all, I would thank

 

  2   you for allowing me to come and speak on behalf of

 

  3   the thousands of innocent Americans that have died

 

  4   as a result of these drugs.

 

  5             I would like to start with an opening,

 

  6   very famous statement, and it says, "The measure of

 

  7   a man is not his strength or how much money he has,

 

  8   or how good he looks or how strong he is, or how

 

  9   powerful he is.  The measure of the man is how

 

 10   noble he is."

 

 11             I want to ask you guys, are you really

 

 12   being noble with your choices, or are you just

 

 13   allowing the drug companies to squeeze by you just

 

 14   because they have a big pocketbook.  This is

 

 15   ridiculous.

 

 16             Do you people have children, do you, do

 

 17   any of you?  Have any of you had anyone that has

 

 18   died on these drugs?  If you have, I am amazed that

 

 19   you guys are even standing here supporting these

 

 20   drug companies.

 

 21             I mean this has never happened in the

 

 22   history of America.  This is a shame and it ought

 

 23   to be stopped today, not next week.

 

 24             MS. TAYLOR:  And God says the same thing.

 

 25   It's in the Bible, Revelations 18, 19 through 24

 

                                                                97

 

  1   makes it clear, sorcery means anarchy in the last

 

  2   days and blood will be running all over the

 

  3   streets.

 

  4             MR. TAYLOR:  Say yes to America's health

 

  5   and no to the drug companies.

 

  6             DR. RUDORFER:  Thank you both.

 

  7             We are going to move on to speaker Number

 

  8   11, Shannon Baker.

 

  9                          Shannon Baker

 

 10             MS. BAKER:  My name is Shannon Baker and I

 

 11   have no financial ties to the pharmaceutical

 

 12   industries, nor am I here to complain about my

 

 13   daughter's side effects, adverse reactions, or

 

 14   withdrawal symptoms.  I am here because she is no

 

 15   longer alive.

 

 16             I know you have all got pictures.  I am

 

 17   here because today, I am representing the love that

 

 18   my daughter had for life and to be her voice and

 

 19   the voice of all the other children who their

 

 20   voices have been silenced by these drugs.

 

 21             Their deaths have been so senseless and

 

 22   needless.  I am here speaking in front of you,

 

 23   hoping that you will go the right direction and ban

 

 24   these drugs for children.  There needs to be no

 

 25   more senseless and needless deaths because of these

 

                                                                98

 

  1   drugs.

 

  2             Thank you.

 

  3             DR. RUDORFER:  Thank you.

 

  4             Our next speaker, Number 12, please.

 

  5                            Dawn Rider

 

  6             MS. RIDER:  My name is Dawn Rider and I am

 

  7   here to tell you my story, and I represent, as

 

  8   president of ASPIRE, more than 11,000 persons who

 

  9   are all named on the Eli Lilly and Prozac petition,

 

 10   which a copy has been given to the panel.

 

 11             We have been educated to believe that

 

 12   mental, emotional, and behavioral disorders are

 

 13   caused by chemical imbalances in the brain.  The

 

 14   fact is that this is only theory, and this theory

 

 15   is pushed on us as if it were the absolute truth.

 

 16             The reality is that the best of scientists

 

 17   do not completely understand the complex inner

 

 18   actions of the myriad chemicals in our brains.

 

 19   Those of us who elect to believe this theory and

 

 20   subject ourselves to treatment become guinea pigs

 

 21   in an ongoing experiment.

 

 22             I know this from personal experience.  I

 

 23   trusted our family doctor when he explained that

 

 24   depression is caused by a chemical imbalance.  We

 

 25   trusted him when he determined that Paxil was right

 

                                                                99

 

  1   for my husband, and Prozac for my son.

 

  2             We weren't educated enough at that time to

 

  3   ask him to provide us with the test results that

 

  4   proved which chemicals were being balanced.

 

  5             I am not going to go into details of what

 

  6   happened to our family.  I have given you all

 

  7   documentation, it's very painful.  Suffice it to

 

  8   say that my beautiful 14-year-old son is now dead,

 

  9   and when we discovered the problems with these

 

 10   drugs, we decided it would be better for my husband

 

 11   to suffer through depression than end up dead like

 

 12   our son, and we found out that he could not get off

 

 13   of Paxil.

 

 14             He went through over a year of hell before

 

 15   he was able to finally withdraw from the drug, and

 

 16   in the process it destroyed our marriage of over 20

 

 17   years.

 

 18             I say with no apology whatsoever that

 

 19   these SSRI drugs destroyed what was once a loving

 

 20   and vibrant family. Why do we believe that street

 

 21   drugs like heroin and LSD can lead to outcomes such

 

 22   as this, yet, we won't accept that legally

 

 23   prescribed drugs, working on the same

 

 24   neurochemicals, can result in horrific crimes

 

 25   against persons and property?

 

                                                               100

 

  1             Why do we accept that a drug like

 

  2   penicillin, beneficial as it is for some, can prove

 

  3   fatal for others?  We fail to accept that these

 

  4   drugs can have paradoxical effects.  These drugs

 

  5   are not safe for everyone.

 

  6             They should be labeled with the strongest

 

  7   of precautions and dispensed only by trained

 

  8   physicians who have time to adequately monitor the

 

  9   patient.  Most doctors do not have time for this

 

 10   level of care.

 

 11             Also, patients should be required to sign

 

 12   letters of informed consent.  Please carefully

 

 13   consider the documentation that I have left with

 

 14   you and look at the faces of those that are here

 

 15   today and the faces that out in the hall, those

 

 16   children who cannot speak for themselves because

 

 17   they are dead.  They are not merely anecdotal

 

 18   evidences.

 

 19             There is a preponderance of evidence that

 

 20   will be presented before you today.  Please

 

 21   consider it carefully and do the right thing.

 

 22             Thank you.

 

 23             DR. RUDORFER:  Thank you.

 

 24             We are up to Number 13.

 

 25                           Sara Bostock

 

                                                               101

 

  1             MS. BOSTOCK:  I have slides, so please

 

  2   look at the screen.

 

  3             My daughter Cecily had only been taking

 

  4   Paxil for two weeks before she died, during which

 

  5   time her condition greatly worsened.

 

  6             By the day of her death, was pale, unable

 

  7   to sleep, almost unable to converse, and in a

 

  8   frightened, agitated state, jumping at the

 

  9   slightest noise.  That night she got up and without

 

 10   turning on any lights, went into our kitchen only

 

 11   40 feet from where I was half asleep.  She stabbed

 

 12   herself twice in the chest with a large chef's

 

 13   knife.  The only noise was a slight yelp and a

 

 14   thump when she fell on the floor.

 

 15             This was a young woman who had everything

 

 16   to live for.  She had just completed applications

 

 17   to grad school and received a large pay increase

 

 18   the month before.

 

 19             She had a boyfriend who loved her and

 

 20   scores of wonderful friends.  She had never been

 

 21   suicidal.  To die in this violent, unusual fashion

 

 22   without making a sound after  the marked worsening

 

 23   of her condition led me to believe that Paxil must

 

 24   have put her over the edge.

 

 25             Her autopsy revealed she had a very high

 

                                                               102

 

  1   blood level of Paxil, which reflects poor

 

  2   metabolization and is a feature common to many of

 

  3   these suicides.  I believe this induced an

 

  4   intensely dissociative state, perhaps even

 

  5   sleepwalking.  SSRIs suppress rapid eye movement

 

  6   and block the muscle paralysis which occurs in this

 

  7   stage of sleep.

 

  8             The whole regulation of waking, sleeping,

 

  9   dreaming occurs in the brain stem where the

 

 10   serotonin neurons are clustered and where SSRIs are

 

 11   having their impact.  Patients taking SSRIs had

 

 12   rapid eye movement during non-REM sleep and while

 

 13   awake when they were not paralyzed.  This atypical

 

 14   REM is often associated with strange behaviors

 

 15   including hallucinations.

 

 16             The effects of SSRIs on sleeping, waking,

 

 17   unconsciousness itself are ill understood.  From

 

 18   accounts of people under the influence of these

 

 19   drugs, I believe SSRIs can alter consciousness in

 

 20   some mysterious and frightening way that is not

 

 21   normally seen even in mental illness.  I am certain

 

 22   this is what happened to my daughter.

 

 23             Untold thousands have died because of the

 

 24   drug companies and the FDA's failure to heed the

 

 25   evidence over the past 17 years.

 

                                                               103

 

  1             DR. RUDORFER:  Thank you.

 

  2             Again, I apologize for the short time.

 

  3             Number 14, please.

 

  4                       Vera Hassner Sharav

 

  5             MS. SHARAV:  I am Vera Sharav and I am

 

  6   president of the Alliance for Human Research

 

  7   Protection.

 

  8             The family testimonies that you are

 

  9   hearing today are not anecdotes.  They are

 

 10   corroborated by a Harvard review of children's

 

 11   medical charts, which found that within three

 

 12   months of treatment on an SSRI, 22 percent suffered

 

 13   drug-induced adverse psychiatric effects, and

 

 14   overall, 74 percent of children suffered adverse

 

 15   events during the course of treatment.

 

 16             The FDA has known for years, but failed to

 

 17   reveal that antidepressants consistently fail to

 

 18   demonstrate a benefit in children.  At least 12 of

 

 19   15 trials failed.  The FDA has known and failed to

 

 20   warn physicians and the public that SSRIs increase

 

 21   the risk of suicide and hostility in children.

 

 22             FDA's 1996 Zoloft review found "7-fold

 

 23   greater incidence of suicidality in children

 

 24   treated with Zoloft than adults."  The British Drug

 

 25   Regulatory Authority reviewed the evidence, which

 

                                                               104

 

  1   is not being shown in this meeting, and they

 

  2   determined that the risks far outweigh any

 

  3   benefits.  They took action to protect children.

 

  4   When is the FDA going to take action?

 

  5             The FDA is foot dragging, equivocating,

 

  6   and tinkering with definitions while children are

 

  7   dying.  The San Francisco Chronicle reports that

 

  8   the FDA has barred its own medical reviewer who

 

  9   reviewed more than 20 trials involving 4,000

 

 10   children, and his findings confirmed the British

 

 11   finding, which is that SSRIs increase the risk of

 

 12   suicide.

 

 13             DR. RUDORFER:  Thank you.

 

 14             If we could have speaker 16, please.

 

 15                         Cynthia Brockman

 

 16             MS. BROCKMAN:  Thank you for allowing me

 

 17   to address you about the 1999 Zoloft-induced drug

 

 18   reactions that my son Chris had at 16, resulting in

 

 19   a woman's death and a life sentence for him.

 

 20             My son and I want to express sincere

 

 21   sorrow for that death.  Our sympathies also extend

 

 22   to all victims of SSRI's deadly mind-altering

 

 23   effects.

 

 24             The medical community has tolerated mental

 

 25   health care in which patients are worse off after

 

                                                               105

 

  1   treatment than before with the worst cases ending

 

  2   in death.

 

  3             I urge you to ban SSRI use in children,

 

  4   and not to let another life be destroyed by lack of

 

  5   adequate SSRI regulation.

 

  6             Chris took Zoloft or Adderall,

 

  7   deteriorated from drug-induced akathisia, could not

 

  8   bear adverse symptoms of inner turmoil, loss of

 

  9   conscious behavior.  He described overpowering drug

 

 10   effects, his uncontrollable fits of anger, pitches

 

 11   and voices setting him off, not wanting to be

 

 12   touched, feeling horrible all over his body, not

 

 13   being in reality.

 

 14             After his offense, his drug reactions

 

 15   stopped, went off all SSRIs for about a year, but

 

 16   restarted when depressed and put on Zoloft again.

 

 17   Prison doctors ignored warnings, forced him to take

 

 18   harmful drugs drugging him into hallucinating,

 

 19   irrational, suicidal state.

 

 20             May 2002, I met with the Texas House

 

 21   Committee on Corrections who ordered prison doctors

 

 22   to correct this health crisis caused by these

 

 23   drugs.  Various drugs had triggered severe

 

 24   suicidal, homicidal symptoms for about two years in

 

 25   a clinical setting of doctors starting and stopping

 

                                                               106

 

  1   his meds.

 

  2             When doctors stopped all drugs, all

 

  3   symptoms disappeared.  Doctors released Chris as

 

  4   recovered from the prison psych hospital to a

 

  5   regular unit May 2003.  Chris has not had any psych

 

  6   drugs since.

 

  7             These clinical events show dangerous

 

  8   reactions caused by SSRI-induced psychosis through

 

  9   challenge, de-challenge, re-challenge.  Medical

 

 10   experts said Chris would not have been suicidal,

 

 11   homicidal had he not been reacting to SSRI drugs.

 

 12             Dr. O'Donnell concluded Chris' offense was

 

 13   from combined toxic drug effects which altered

 

 14   behavior, enhanced violent thoughts and actions,

 

 15   impaired judgment, was unable to form intent.

 

 16             Citizens Commission on Human Rights

 

 17   confirmed SSRIs caused his symptoms.  Now Chris

 

 18   take omega-3 fatty acids and fish oil to restore

 

 19   his mental health that was damaged from SSRIs.  He

 

 20   is doing well without medications, and I thank

 

 21   Jesus Christ for that.

 

 22             Please ban these drugs and their use in

 

 23   children.

 

 24             Thank you.

 

 25             DR. RUDORFER:  Thank you.

 

                                                               107

 

  1             We will move on now to Number 18, please.

 

  2                           Todd Shivak

 

  3             MR. SHIVAK:  Good morning.  We are Todd

 

  4   and Eileen Shivak.  We do not have any financial

 

  5   relationship to anyone here.

 

  6             Our story is much like the cases everyone

 

  7   else here today is bringing forward to you.

 

  8             Our son Michael was 11 when he was

 

  9   prescribed Paxil for what was diagnosed as

 

 10   depression.  The consequences of this still live

 

 11   with us today.  Thank God he is alive and with us

 

 12   today, but Michael is afraid of his doctors, how

 

 13   can he trust what they will give him next.

 

 14             He is afraid of the police.  He has been

 

 15   wrestled down, handcuffed and taken to jail.  The

 

 16   police are supposed to protect us and look what

 

 17   they have done to him.

 

 18             It is difficult for him to trust his

 

 19   teachers. They still look at Michael as a

 

 20   troublemaker even though he currently is an A/B

 

 21   student with much improving grades.  His peers

 

 22   still think of him as a freak, the kid who tried to

 

 23   slash his wrists while in class.

 

 24             As parents, our most important job is to

 

 25   protect our kids.  We thought we were doing the

 

                                                               108

 

  1   right thing.  The doctors convinced us that taking

 

  2   these drugs was the only thing that we could do for

 

  3   Michael.  Now, Michael wonders whether we are going

 

  4   to have him arrested, sentenced, physically

 

  5   restrained and punished again.  If he can't trust

 

  6   his parents, who can he trust?

 

  7             Our daughter, Catherine, was 5 years old

 

  8   at the time.  She witnessed firsthand some of the

 

  9   most terrifying sights that I have ever had to deal

 

 10   with.  Our family is finally getting back to the

 

 11   loving family we once were, but the fear of what

 

 12   happened still haunts us.

 

 13             Worse yet, how could all the doctors not

 

 14   recognize what was happening?  Michael saw three

 

 15   different social workers, two different

 

 16   psychiatrists, and went through at least four

 

 17   different emergency room psychological evaluations

 

 18   in two different hospitals.

 

 19             We are here to plead that you do something

 

 20   to stop the prescriptions of these drugs, so that

 

 21   no one else has to go what we are all going

 

 22   through.  It is impossible to describe the pain and

 

 23   utter helplessness we all felt watching Michael

 

 24   suffer, watch him cry, take up weapons against us,

 

 25   and beg us to let him die.  How do you erase the

 

                                                               109

 

  1   picture of your child trying to run in front of a

 

  2   moving car?

 

  3             Please save our children from this drug.

 

  4             DR. RUDORFER:  Thank you.

 

  5             If we can have speaker 19, please.

 

  6                           Andy Vickery

 

  7             MR. VICKERY:  Good morning.  My name is

 

  8   Andy Vickery and I am a trial lawyer from Houston,

 

  9   Texas.  For the last eight years, I have

 

 10   represented parents who lost their children to

 

 11   suicide induced by these drugs.  You have heard

 

 12   from two of my clients this morning already and

 

 13   will hear from another.

 

 14             I only have two minutes and I can tell you

 

 15   a lot more than two minutes.  The title of the

 

 16   paper that I filed with you is "Needle in the

 

 17   Haystack."  I applaud your desire to look at the

 

 18   randomized clinical trials comprehensively to see

 

 19   if they confirm the signal that Dr. Katz

 

 20   acknowledged exists.

 

 21             I applaud that, however, I am concerned as

 

 22   Lilly was told in 1990 that you are looking for a

 

 23   needle in a haystack, you are off on a wild goose

 

 24   chase.  These trials were not designed to detect

 

 25   suicidality, they did not use the Beck Suicide

 

                                                               110

 

  1   Ideation Scale which would make the kind of refined

 

  2   measurements that the epidemiologist gentleman who

 

  3   spoke earlier said are needed.  They did not use

 

  4   the Barnes Scale, as Dr. Mann himself had

 

  5   recommended in a '91 article to measure treatment

 

  6   emergent akathisia.

 

  7             They weren't designed to answer the

 

  8   problem, and in 1990 or '91, when Lilly met -- and

 

  9   you have the handwritten notes of this in the

 

 10   materials I gave you -- when they met with outside

 

 11   consultants including Dr. Jerold Rosenbaum, he

 

 12   said, "There is a data problem, you are looking for

 

 13   a needle in a haystack."

 

 14             Find these vulnerable people and

 

 15   rechallenge them. Please look at the way Lilly

 

 16   sought to study this issue in 1990.  They followed

 

 17   a protocol by Charles Beasley that said don't use

 

 18   RCTs, don't use epi studies, find these people and

 

 19   rechallenge them.  That was done by Anthony

 

 20   Rothschild who said these patients need to be

 

 21   reassured it's not them.

 

 22             In the meantime, because the signal is

 

 23   there, please issue warnings; while you look at the

 

 24   data, issue warnings.

 

 25             DR. RUDORFER:  Thank you.

 

                                                               111

 

  1             We are up to speaker 20.

 

  2                      Rosie Carr Meysenburg

 

  3             MS. MEYSENBURG:  My name is Rosie Carr

 

  4   Meysenburg. I am from Dallas, Texas.  I have no

 

  5   financial ties with anybody but my husband of 40

 

  6   years.

 

  7             In my handout, I have highlighted what I

 

  8   am speaking about here.

 

  9             The first paper is a personal letter from

 

 10   Dr. Peter S. Jensen.  At that time, he was the head

 

 11   of Child & Adolescent Disorders Research Branch of

 

 12   the NIMH, the National Institute of Mental Health.

 

 13   He said that research indicates that

 

 14   antidepressants for depressed adolescents are not

 

 15   very effective.

 

 16             The second paper is a personal letter from

 

 17   Dr. Larry S. Goldman, Director of the AMA, the

 

 18   American Medical Association.  He writes physicians

 

 19   have known for many years the dangers of giving any

 

 20   antidepressant to patients with certain disorders.

 

 21   There is a substantial risk of precipitating mania

 

 22   or psychosis.

 

 23             The last item is a journal article from

 

 24   the Journal of Clinical Psychiatry researched at

 

 25   Yale University.  It states that 11 percent of all

 

                                                               112

 

  1   psychiatric hospital admissions were from

 

  2   antidepressant-induced mania and psychosis.

 

  3             It also states another area of research

 

  4   that would be relevant to this issue is the work of

 

  5   Winter and colleagues showing that Prozac and other

 

  6   SSRIs can simulate the effects of LSD.  In other

 

  7   words, this is saying for some people, taking an

 

  8   SSRI is the same as taking LSD.

 

  9             About two million people enter a

 

 10   psychiatric hospital every year, 11 percent then is

 

 11   over 200,000 people a year who have an

 

 12   antidepressant-induced psychosis and who are

 

 13   hospitalized.  Not all are hospitalized.  Some of

 

 14   them have either committed suicide, a homicide, or

 

 15   a murder/suicide.

 

 16             DR. RUDORFER:  Thank you.

 

 17             Number 21, please.