perspec tives
benefit ratios, practical clinical trials serve
as a robust platform for identifying mod-
erators of treatment outcome, including
biomarkers/biosignatures, as well as for
tests of multistage treatment strategies
using dynamic treatment regimes. In
depression, an informative PCT would
contrast fluoxetine with bupropion—
medications from two classes, with one
(bupropion) that at least clinically seems
to have a lower risk for suicidal events. We
also need trials that emphasize understand-
ing mechanisms (mediation) of treatment
response using tools from cellular and
molecular neuroscience and from cogni-
tive neuroscience (e.g., deep phenotyping).
In the aforementioned fluoxetine-vs.-
bupropion PCT, a biomarker/biosigna-
ture aim might be doubly informative if it
yielded an intervention biomarker for sui-
cidality vulnerability. When combined with
drug, biologic, and device development
efforts for new molecular targets, such a
two-pronged effort for both medications
and psychosocial interventions over the
next decade should yield truly personal-
ized and preventive treatments for mental
illness across the life span.
ACKNOWLEDGMENTS
This work was supported by National Institute of
Mental Health (NIMH) grants 1 K24 MHO1557,
1 N01 MH80008, 1 U01 MH64107, 2R01 MH55121,
1R01MH079154, and 1 P30 MH66386 and by a
National Alliance for Research on Schizophrenia
and Depression Distinguished Senior Investigator
Award. This article meets all applicable Duke
University and federal guidelines for research.
Benefits Exceed Risks of Newer Antidepressant
Medications in Youth—Maybe Not
WZ Potter1
The major challenge for making evidence-
based decisions on benefit vs. risk is the
highly variable quality of relevant data. In
their section of this Point/Counterpoint,
Drs. March and Vitiello argue from an
expert academic research and National
1Translational Neuroscience, Merck Research Laboratories, North Wales, Pennsylvania, USA. Correspondence: WZ Potter (william_potter@merck.com)
doi:10.1038/clpt.2009.173
Clinical pharmacology & Therapeutics | VOLUME 86 NUMBER 4 | OCTOBER 2009 357
CONFLICT OF INTEREST
J.S.M. has served as a consultant or scientific
advisor to Pfizer, Eli Lilly, Wyeth, GlaxoSmithKline,
Bristol-Myers Squibb, and MedAvante. He has
received research support from Eli Lilly and
Pfizer and study drug for an NIMH-funded study
from Eli Lilly and Pfizer and is an equity holder in
MedAvante. He receives royalties from Guilford
Press, Oxford University Press, and MultiHealth
Systems and research support from the NIMH. B.V.
declared no conflict of interest.
© 2009 ASCPT
1. Bridge, J.A., Salary, C.B., Birmaher, B., Asare,
A.G. & Brent DA. The risks and benefits
of antidepressant treatment for youth
depression. Ann. Med. 37, 404–412 (2005).
2. Emslie, G.J. et al. A double-blind, randomized,
placebo-controlled trial of fluoxetine in
children and adolescents with depression.
Arch. Gen. Psychiatry 54, 1031–1037 (1997).
3. TADS. Fluoxetine, cognitive-behavioral
therapy, and their combination for
adolescents with depression: Treatment for
Adolescents With Depression Study (TADS)
randomized controlled trial. JAMA 292, 807–
820 (2004).
4. Emslie, G.J. et al. Fluoxetine for acute
treatment of depression in children
and adolescents: a placebo-controlled,
randomized clinical trial. J. Am. Acad. Child
Adolesc. Psychiatry 41, 1205–1215 (2002).
5. Vitiello, B. et al. How can we improve the
assessment of safety in child and adolescent
psychopharmacology? J. Am. Acad. Child
Adolesc. Psychiatry 42, 634–641. 2003.
6. Hammad, T.A., Laughren, T. & Racoosin, J.
Suicidality in pediatric patients treated with
antidepressant drugs. Arch. Gen. Psychiatry 63,
332–339 (2006).
7. POTS. Cognitive-behavior therapy, sertraline,
and their combination for children and
adolescents with obsessive-compulsive
disorder: the Pediatric OCD Treatment Study
(POTS) randomized controlled trial. JAMA 292,
1969–1976 (2004).
Institute of Mental Health (NIMH) posi-
tion reflecting their leadership in the field.1
They address the imperative of making a
treatment decision when presented with a
child or adolescent who meets diagnostic
criteria for major depression. Do the data
8. March, J., Silva, S. & Vitiello, B; TADS team. The
Treatment for Adolescents with Depression
Study (TADS): methods and message at 12
weeks. J. Am. Acad. Child Adolesc. Psychiatry
45, 1393–1403 (2006).
9. March, J. & Vitiello, B. Clinical messages
from the Treatment for Adolescents with
Depression Study (TADS). Am. J. Psychiatry (in
press).
10. Walkup, J.T. et al. Cognitive behavioral
therapy, sertraline, or a combination in
childhood anxiety. N. Engl. J. Med. 359, 2753–
2766 (2008).
11. Gibbons, R.D. et al. Early evidence on the
effects of regulators’ suicidality warnings on
SSRI prescriptions and suicide in children and
adolescents. Am. J. Psychiatry 164, 1356–1363
(2007).
12. Gibbons, R.D., Hur, K., Bhaumik, D.K. & Mann,
J.J. The relationship between antidepressant
medication use and rate of suicide. Arch. Gen.
Psychiatry 62, 165–172 (2005).
13. Leckman, J.F. & King, R.A. A developmental
perspective on the controversy surrounding
the use of SSRIs to treat pediatric depression.
Am. J. Psychiatry 164, 1304–1306 (2007).
14. National Advisory Mental Health Council.
Transformative Neurodevelopmental Research
in Mental Illness. (National Institute of Mental
Health, Washington, DC, 2008).
15. Califf, R.M., Rasiel, E.B. & Schulman, K.A.
Considerations of net present value in policy
making regarding diagnostic and therapeutic
technologies. Am. Heart J. 156, 879–885
(2008).
16. DeVeaugh-Geiss, J., et al. Child and adolescent
psychopharmacology in the new millennium:
a workshop for academia, industry, and
government. J. Am. Acad. Child Adolesc.
Psychiatry 45, 261–270 (2006).
17. March, J.S., Silva, et al. The Child and
Adolescent Psychiatry Trials Network (CAPTN).
J. Am. Acad. Child Adolesc. Psychiatry 43, 515–
518 (2004).
18. March, J.S., Silva, S.G., Compton, S., Shapiro,
M., Califf, R. & Krishnan, R. The case for
practical clinical trials in psychiatry. Am. J.
Psychiatry 162, 836–846 (2005).
on which their expert opinion is based
support the level of certainty needed to
resolve current debates? Given the failure
of the newer antidepressants to separate
from placebo in >65% of recent phase III
fixed-dose trials in adults, coupled with
perspec tives
the modest effect size when they do, there
is a low likelihood of marked benefit in
any particular subject.2 The same seems
to be the case in adolescents. In children
diagnosed as depressed, the sole drug to
show separation from placebo is fluoxet-
ine. As Drs. March and Vitiello note, it is
only in anxiety and obsessive-compulsive
disorders that a robust effect of the drug
class is observed. Because, as they note, the
risk for suicidal events is much greater for
depression, the discussion here focuses on
the risk–benefit in this disorder.
The placebo-controlled database across
all antidepressant trials in adolescents
and children is too small to yield much
certainty in estimating benefit for the
wider population in this age range. As
reviewed by Bridge et al.,3 the total num-
bers of patients across published and
unpublished studies they could assess
were 1,344 on drug vs. 1,157 on placebo.
Of the total on drug, 368 patients were
contributed from paroxetine trials, with a
mean 58.7% response rate (much or very
much improved, not remitted) vs. 52.9%
on placebo, leading to a number needed to
treat of 20 to find one subject who benefits
more than on placebo. Because drug-vs.-
placebo trials are designed to provide the
greatest sensitivity possible in terms of
showing a drug effect, and because recent
such trials in adolescents show an increase
in response to placebo but not drug,4 one
has little confidence about degree of ben-
efit when generalizing to the general clini-
cal population.
Accurately estimating meaningful
risks of antidepressants in children is
also problematic, as it is even in adults.
Although the field does use standardized
measures of efficacy, we have not thus
far done so to track side effects of anti-
depressants outside of central laboratory
or electrocardiographic readings. The
detection of other events, ranging from
headaches to suicidal attempts, is proto-
col- and often site-specific. Site specificity
arises when details such as timing, staff
expertise, and approach to eliciting possi-
ble side effects are not precisely specified
and monitored. Thus, one can challenge
the interpretation of the meta-analyses
and criteria for class effects made by the
FDA when it compares rates of “suicid-
ality” across antidepressants and, most
358 VOLUME 86 NUMBER 4 | OCTOBER 2009 | www.nature.com/cpt
recently, antiepileptics. In the absence of
prospective controlled studies in large
cohorts using a standardized instru-
ment for ascertaining adverse subjective
sensations, thoughts, and behaviors, it is
extremely difficult to consistently show
that risk on one treatment is different
from that on another or that on placebo.
Judgments of risk are therefore made on
the basis of limited imperfect data and
invite the taking of extreme positions in
the press and elsewhere.
What do we know about assessing risk
in the pediatric population? Apart from
the NIMH-funded studies in obsessive-
compulsive disorder, anxiety, and depres-
sion,5 there are no systematic data beyond
those generated in registration or label
extension studies. In these, potentially
relevant pharmacokinetic data are sparse
as related to either efficacy or side effects,
further limiting our ability to interpret
the data.6 Of special concern with psy-
choactive drugs in youth are effects on
maturation, which has received greatest
focus when attention deficit hyperactiv-
ity disorder is concerned, as reflected by
recent studies on the norepinephrine
uptake inhibitor atomoxetine,7 which
presumably would also be active as an
antidepressant. Whatever the theoretical
possibilities, even something as concep-
tually simple as testing whether the side-
effect profile of newer antidepressants
varies across the child–adolescent–adult
age range remains to be done in an ade-
quately powered direct comparison with
standardized measures. What about the
debate as to whether an increase in algo-
rithm-defined suicidality associated with
the newer antidepressants is a real risk in
the absence of direct evidence linking it
to completed suicides? Even if one accepts
the meta-analytical methods used by the
FDA to conclude that SSRIs and nonse-
lective SRIs as a class are associated with a
twofold increased risk of suicidal ideation
and/or behavior,8 the implications of the
finding remain open. Several ecological
studies have reported an overall protective
effect of SSRIs from completed suicide
in pediatric and young-adult subjects.
Moreover, as recently shown by Gibbons
et al.,9 various statistical approaches to
spontaneous adverse-event reports from
postmarketing surveillance data show
that newer antidepressants are associated
with lower rates of suicide than are older
antidepressants.
Moreover, an argument can be made
that increased adolescent suicide rates in
some populations reflect a decreased use
of antidepressants secondary to the FDA-
mandated black-box warning in late 2004
of a special pediatric risk of suicidality.9,10
However, cause-and-effect relationships
underlying changes in prescribing prac-
tice are difficult to establish. What could
explain, for instance, a reduced rate of
antidepressant monotherapy for children
and adolescents in favor of increased
polypharmacy during the 2001–2005
period?11 The limits of what can be con-
cluded when using prescription databases
to relate drug use to events in a population
were recently highlighted by FDA scien-
tists when debating a possible association
between atypical antipsychotic use and
sudden cardiac death.12
What would it take to provide a rea-
sonable estimate of whether the newer
antidepressants increase suicide in the
broader pediatric population? The largest
study to explore the relative risk of drug-
associated suicide involves antipsychotic
use in adult schizophrenics, a population
with a substantially higher base rate of
suicide than that with pediatric depres-
sion. As reviewed at a recent FDA Advi-
sory Panel Hearing, approximately 5,000
patients per group were randomized to
either sertindole or risperidone for an
initial treatment period, then followed for
1,200 days “under normal conditions of
use.” All-cause mortality was the primary
end point, with cause-specific mortality,
cardiac and suicide, as secondary end
points.13 There were 64 and 61 deaths in
the sertindole and risperidone cohorts,
respectively. Cause-of-death classification
varied between judgment of an independ-
ent safety committee vs. Medical Diction-
ary for Regulatory Activities (MedDRA)
coding, with the former yielding a highly
significant (P < 0.002) increase in cardiac
deaths on sertindole. In contrast, there
were 9 suicides on sertindole (0.14 per
100 years of patient exposure) vs. 19 on
risperidone (0.26 per 100 years of patient
exposure), for a hazard ratio of 0.50
(P < 0.09). Thus, even in adult schizo-
phrenic patients at high risk for suicide,

5,000 patients per arm did not generate
enough events to achieve significance for a
numerically large (0.5) hazard ratio. Small
numbers of events (deaths) and variabil-
ity around method of classification make
for low-confidence conclusions. It would
require tens of thousands of pediatric
subjects followed for years with some to-
be-determined design to provide even a
moderate confidence estimate of com-
pleted-suicide risk attributable to antide-
pressant use.
What can be practically done to have
more confidence that we can either (i)
select individuals in whom sufficient
benefit is likely to outweigh any risk of
negative physiological or behavioral con-
sequences or (ii) establish that the long-
term risk is so low as to argue for treating
a wider population to increase chances of
capturing those who might benefit from
the treatment?
A workshop on suicidality held by the
Institute of Medicine’s Forum on Neuro-
science on 17 June 2009 focused on a path
for industry, academia, and the FDA to
agree on a common instrument for meas-
uring suicidality (a principle that could
be extended to any other potential risk of
interest), to standardize it in multisite trials
to the same extent to which we standardize
primary-efficacy measures, and to devise a
follow-up plan for pooling data to generate
as quickly as possible enough events from
randomized clinical trials to learn whether
the measure has any predictive value. Such
a collaborative effort would be a first for
the field of psychopharmacology—an
endeavor in which government, industry,
and academia try to address an important
Clinical pharmacology & Therapeutics | VOLUME 86 NUMBER 4 | OCTOBER 2009 359
risk–benefit question for society that goes
beyond what is required for approval.
Another approach to assessing the
population risk of serious and rare events
is through practical clinical trials with
systematic adverse-event assessments
captured by an electronic case-report-
form workflow. Some might say that
any such efforts are premature and we
should wait until quantitative biochemi-
cal, functional brain imaging, and genetic
measures ensure that we are selecting sub-
jects with a higher likelihood of needing
drug and a low likelihood of responding
to placebo. Identifying such measures,
however, will take much longer than the
proposed approach to testing whether sig-
nals detected in clinical trials do or do not
later predict serious behaviors (suicide) or
physiological consequences (e.g., stunted
growth, altered sexual maturation, or
abnormal brain size or structure). Without
committing to standardized quantifica-
tion of  “side effects” and to paradigms for
assessing their longer-term consequences,
we default to majority expert opinion on
the risk–benefit of psychopharmacological
agents such as antidepressants in children
and adolescents. If we want to have more
confidence, we should put expert opinion
to the test in a prospective, collaborative
manner using tools and methodologies
available in the near term.
CONFLICT OF INTEREST
The author is employed by Merck.
© 2009 ASCPT
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A.G. & Brent, D.A. The risks and benefits of
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Ann. Med. 37, 404–412 (2005).
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Psychiatry 64, 1132–1143 (2007).
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trials in juvenile major depression. J. Child
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Suicidality in pediatric patients treated with
antidepressant drugs. Arch. Gen. Psychiatry 63,
332–339 (2006).
8. Gibbons, R.D. et al. Early evidence on the
effects of regulators’ suicidality warnings on
SSRI prescriptions and suicide in children and
adolescents. Am. J. Psychiatry 164, 1356–1363
(2007).
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Committee (PDAC) Meeting. Product:
Serdolect®<http://www.fda.gov/
downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
PsychopharmacologicDrugsAdvisory
Committee/UCM161901.pdf> (9 March 2009).