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