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