The Science and Ethics of Antipsychotic Use in Children

218 Pages·2015·6.289 MB·English

by  Di Pietro, Nina, Illes, Judy

The Science and Ethics of
Antipsychotic Use in Children
The Science and Ethics
of Antipsychotic Use
in Children
Edited by
Nina Di Pietro and Judy Illes
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Contributors
Mai Berger Sleep/Wake Behaviour Clinic & Research Lab, BC Children’s
Hospital, Division of Developmental Pediatrics, Department of Pediatrics,
Faculty of Medicine, University of British Columbia; and Person Centered
Medicine, Treatable Intellectual Disability Endeavour in British Columbia
(TIDE BC), Vancouver, British Columbia, Canada
Bruce Carleton BC Children's Hospital, Division of Translational Therapeutics,
Department of Pediatrics, Child & Family Research Institute, University of
British Columbia, Vancouver, British Columbia, Canada
Lorrie Chow Provincial Mental Health Metabolic Program, BC Children’s
Hospital, Vancouver, British Columbia, Canada
Jana Davidson Children’s & Women’s Mental Health and Substance Use
Services, Children’s and Women’s Health Centre of BC, Provincial Health
Services Authority; and Department of Psychiatry, University of British
Columbia, Vancouver, British Columbia, Canada
Nina Di Pietro National Core for Neuroethics, Division of Neurology, Faculty
of Medicine, University of British Columbia, Vancouver, British Columbia,
Canada
Dean Elbe Division of Children’s and Women’s Mental Health, BC Mental
Health & Addiction Services; Department of Pharmacy, BC Children’s
Hospital; Faculty of Pharmaceutical Sciences, University of British
Columbia; and Child & Adolescent Mental Health, BC Children’s Hospital,
Vancouver, British Columbia, Canada
David Gardner College of Pharmacy, Department of Psychiatry, Dalhousie
University, Halifax, Nova Scotia, Canada
Judy Illes National Core for Neuroethics, Division of Neurology, Faculty of
Medicine, University of British Columbia, Vancouver, British Columbia,
Canada
Osman Ipsiroglu Sleep/Wake Behaviour Clinic & Research Lab, BC Children’s
Hospital, Division of Developmental Pediatrics, Department of Pediatrics,
Faculty of Medicine, University of British Columbia, Vancouver; Faculty
of Science, Thompson Rivers University, Kamloops; and Person Centered
Medicine, Treatable Intellectual Disability Endeavour in British Columbia
(TIDE BC), Vancouver, British Columbia, Canada
Kristine Kuss Provincial Mental Health Metabolic Program, BC Children’s
Hospital, Vancouver, British Columbia, Canada
ix
x Contributors
Stan Kutcher Department of Psychiatry, Dalhousie University; Sun Life Chair
in Adolescent Mental Health, IWK Health Centre and Dalhousie University;
and WHO Collaborating Center, IWK Health Centre—Maritime Outpatient
Psychiatry, Halifax, Nova Scotia, Canada
Tami Lin Sleep/Wake Behaviour Clinic & Research Lab, BC Children’s
Hospital, Division of Developmental Pediatrics, Department of Pediatrics,
Faculty of Medicine, University of British Columbia; and Person Centered
Medicine, Treatable Intellectual Disability Endeavour in British Columbia
(TIDE BC), Vancouver, British Columbia, Canada
Edel Mc Glanaghy National Core for Neuroethics, Division of Neurology,
Faculty of Medicine, University of British Columbia, Vancouver, British
Columbia, Canada
Andrea Murphy College of Pharmacy, Department of Psychiatry, Dalhousie
University, Halifax, Nova Scotia, Canada
Tim F. Oberlander Department of Pediatrics, School of Population and Public
Health, University of British Columbia, Vancouver, British Columbia,
Canada
Iliana Garcia-Ortega Mathison Centre for Mental Health Research and
Education, University of Calgary, Calgary, Alberta, Canada
Constadina Panagiotopoulos BC Children’s Hospital, Provincial Health Services
Authority; and Department of Pediatrics, University of British Columbia,
Vancouver, British Columbia, Canada
Tamara Pringsheim Department of Clinical Neurosciences, Psychiatry,
Pediatrics and Community Health Sciences, University of Calgary, Calgary,
Alberta, Canada
Rebecca Ronsley BC Children’s Hospital, University of British Columbia,
Vancouver, British Columbia, Canada
Sylvia Stockler Division of Biochemical Diseases, Department of Pediatrics,
Faculty of Medicine, University of British Columbia; and Person Centered
Medicine, Treatable Intellectual Disability Endeavour in British Columbia
(TIDE BC), Vancouver, British Columbia, Canada
Benjamin Wilfond Treuman Katz Center for Pediatric Bioethics, Seattle
Children's Research Institute; and Department of Pediatrics, University of
Washington School of Medicine, Seattle, Washington, USA
Foreword
The use of antipsychotic drugs, in particular second-generation antipsychotics
(SGAs), in children and adolescents is widespread in Canada and other devel-
oped nations, and has increased substantially in the last decade. These agents
are used for a variety of conditions, including psychoses, mood disorders, be-
havioral disorders, and attention-deficit hyperactivity disorder as well as treat-
ment of autism spectrum disorders, tics, sleep disorders, and other nonpsychotic
symptoms. The use of SGAs in these populations is off-label as, with the excep-
tion of certain limited indications for aripiprazole in adolescents, their use has
not been authorized by Health Canada. This is not unusual per se, as the major-
ity of prescription drug use in children is off-label. What makes the situation
with SGAs of particular concern in children and adolescents is (a) the range of
serious or potentially serious adverse effects that are associated with their use,
and (b) the lack of hard evidence for their efficacy. In particular, the metabolic
and cardiovascular adverse effects associated with the use of SGAs raise seri-
ous clinical and ethical questions. These questions are especially pertinent when
considering their use in vulnerable populations. This book, which contains a
series of excellent articles written by leading authorities in their fields, provides
the first extensive evaluation of this complex and important issue available un-
der one cover.
It is important to remember that the off-label use of drugs in specific popu-
lations or disorders is not inherently wrong or unsafe; rather it means that
there is insufficient available evidence to allow the regulatory agency con-
cerned to include the indication in the label (or product monograph). The
term “off-e vidence” might, in fact be more accurate. This highlights a fun-
damental issue in the use of drugs in special populations such as children,
adolescents, and pregnant women, which is the difficulty, both practically and
ethically, in conducting appropriate clinical trials—in particular randomized
controlled trials (RCTs). RCTs are considered the gold standard of evidence-
based medicine and are essentially mandatory for the regulatory approval of
new medicines. Their application in pediatric populations is particularly chal-
lenging, although detailed literature review indicates that many of these trials
are carried out; indeed, regulatory agencies are increasingly mandating them
as part of the post-marketing review process. In addition to improvements in
pediatric clinical trial design there, have been exciting new advances in physi-
ologically based pharmacokinetic modeling, which will undoubtedly lead to
a much stronger evidence base supporting the use of new and existing drugs
in these populations.
xi
xii Foreword
This book provides an important and much-needed resource for researchers,
students, and practitioners, as well as patients and their families. The detailed
analysis and discussion presented in the various chapters will inform the con-
tinuing debate surrounding the appropriateness, or otherwise, of using SGAs
in children and adolescents. It will hopefully inspire further research into this
important issue and ultimately support the development and implementation of
rational, evidence-based policy.
Michael Coughtrie
Faculty of Pharmaceutical Sciences
University of British Columbia
Vancouver, BC, Canada
Acknowledgments
Drs. Di Pietro and Illes gratefully acknowledge NeuroDevNet, Inc. for sup-
porting their work on this book. NeuroDevNet, Inc. is a Canadian Network
of Centres of Excellence dedicated to understanding brain development and
helping children and their families overcome the challenges of neurodevel-
opmental disorders. We also wish to acknowledge the Peter Wall Institute for
Advanced Studies for funding the workshop “Deliberations on the Ethical Use
of Antipsychotic Medications in Children” and the subsequent creation of the
Canadian Working Group on Antipsychotics for Children. Dr. Illes is Canada
Research Chair in Neuroethics. The programs of research at the National
Core for Neuroethics under her direction have been generously enabled by the
Canadian Institutes of Health, the British Columbia Knowledge Development
Fund, the Canadian Foundation for Innovation, the Vancouver Coastal Research
Institute, and other private funders.
xiii
Introduction: A Call for
Partnership
Nina Di Pietro, Judy Illes
There are more than 60 years of clinical evidence demonstrating the benefits
of antipsychotic medications for improving the lives of individuals affected by
serious mental illnesses such as schizophrenia and bipolar disorder. The ben-
efits of these medicines, however, are not without potential risk, ranging from
mild unwanted side effects such as drowsiness to serious complications such
as diabetes. For children and youth,1 the risks are compounded by therapeutic
uncertainties about their effectiveness for treatment of mental health conditions
in this group. Nonetheless, antipsychotics are increasingly being applied to treat
a wide range of emotional and behavioral problems in children, a trend that
is causing many to wonder about how these medications are being used and
prescribed. In this book, we explore the tension between the risk of treatment
and the risk of illness within the context of off-label antipsychotic prescrib-
ing practices. Using a pragmatic neuroethics framework, we build on empirical
research to inform best practices for prescribing antipsychotic medications to
young people. This approach allows for the integration of a variety of medi-
cal, ethical, and sociological perspectives, which are ultimately needed to guide
clinical practice (Racine et al., 2011).
The book is a direct product of the workshop “Deliberations on the Ethical
Use of Antipsychotic Medications in Children” that we held in September 2013
at the University of British Columbia, with the support of the Peter Wall Institute
for Advanced Studies and NeuroDevNet, Inc. The workshop brought together
research and clinical leaders in child psychiatry, ethics, and neuroscience in a
think tank setting to consider the state of the science and ethics of prescribing
antipsychotic medicines for children. From it, we identified critical unanswered
questions and formed the “Canadian Working Group on Antipsychotics for
Children” to address them.
The Working Group weighed in on three key questions:
1. What phenomena account for the increase in prescribing antipsychotics for
children and adolescents?
2. What gaps in knowledge need to be filled in order to begin to address con-
cerns about safety and efficacy?
1 We use the term children to refer to individuals age 0-12 years and youth to refer to individuals
age 13-18 years.
xv
xvi Introduction: A Call for Partnership
3. What are the ethical, legal, and social consequences of increased off-label
use of antipsychotic medications in young people, and where do we go from
here?
The group deliberations under each question are summarized below:
(1) What phenomena account for the increase in prescribing antipsychotics for
children and adolescents?
The Working Group recognized that the reason for the burgeoning off-label
use of antipsychotics in children and youth is likely multifactorial—a phenom-
enon that situates itself within political, sociocultural, and economic arenas (Di
Pietro & Illes, 2014). To date, there has been little attempt to study how or to what
extent any of these arenas may influence prescribing practices within the context
of antipsychotics for children. Evidence is mostly anecdotal and in the form of
news reports in the popular media. The proposed factors that account for the in-
crease in second-generation antipsychotic prescription use, as derived from our
group discussions and supplemented by the scientific literature, are as follows:
i. Wider availability of new antipsychotics on the market in the last
15 years.
Throughout the 1970s and 1980s, the term atypical was synonymous with
clozapine. At the turn of the millennium, however, several new atypical anti-
psychotics were developed and made available on the North American mar-
ket: risperidone (1993), olanzapine (1997), quetiapine (1997), ziprasidone HCl
(2001), aripiprazole (2002), and paliperidone (2006). Soon after the introduc-
tion of these atypical drugs, they quickly became the most studied treatments
for schizophrenia and other indications (Meltzer, 2013). As a result, second-
generation antipsychotic (SGA) use also increased during this time period. For
instance, prescriptions in the province of Manitoba for SGAs went from 1.9 per
1000 in 1999 to 7.4 per 1000 in 2008 (Alessi-Severini et al., 2012). Prior to the
1990s, the level of antipsychotic use among children was relatively constant
(Olfson et al., 2002).
ii. Approval of antipsychotics to treat indications in adolescents.
In 2011, Health Canada approved Abilify® (aripiprazole) for the treatment
of schizophrenia and bipolar disorder in adolescents, making it the first atypical
antipsychotic to be specifically approved for use in children and youth. In the
United States, the FDA approved it for the treatment of irritability in children
with autism as young as age 6. Growing approval for use in minors may con-
tribute to perceptions that antipsychotics are generally safe and effective, even
if evidence for this is limited to older adolescents with serious mental health
conditions.
iii. Emerging clinical trial data supporting antipsychotic use for youths out-
side of approved Health Canada indications.
The empirical basis for the use of SGAs outside of approved Health Canada
indications is supported by a growing number of studies that show that they may
be effective for treating a variety of different mental health problems in children
and adolescents. According to the Cochrane Database of Systematic Reviews,