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
Holiday Inn
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
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
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
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
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.
18 Rachel Adler
19
MS. ADLER: Mr. Chairman, I
respectfully
20
request that my entire remarks be entered in the
21
record. My name is Rachel Adler. I am on the
22