Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B,
Whittington C, Coghill
D, Zhang Y, Hazell P, Leucht S, Cuijpers P, Pu J, Cohen D,
Ravindran AV, Liu Y,
Michael KD, Yang L, Liu L, Xie P. Comparative efficacy and
tolerability of
antidepressants for major depressive disorder in children
and adolescents: a
network meta-analysis. Lancet. 2016 Jun 7. pii:
S0140-6736(16)30385-3.
Abstract
BACKGROUND:
Major depressive disorder is one of the most common mental
disorders in children and adolescents. However, whether to use pharmacological
interventions in this population and which drug should be preferred are still
matters of controversy. Consequently, we aimed to compare and rank
antidepressants and placebo for major depressive disorder in young people.
METHODS:
We did a network meta-analysis to identify both direct and
indirect evidence from relevant trials. We searched PubMed, the Cochrane
Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies'
websites, and international registers for published and unpublished,
double-blind randomised controlled trials up to May 31, 2015, for the acute
treatment of major depressive disorder in children and adolescents. We included
trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine,
escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline,
paroxetine, sertraline, and venlafaxine. Trials recruiting participants with
treatment-resistant depression, treatment duration of less than 4 weeks, or an
overall sample size of less than ten patients were excluded. We extracted the
relevant information from the published reports with a predefined data
extraction sheet, and assessed the risk of bias with the Cochrane risk of bias
tool. The primary outcomes were efficacy (change in depressive symptoms) and
tolerability (discontinuations due to adverse events). We did pair-wise
meta-analyses using the random-effects model and then did a random-effects
network meta-analysis within a Bayesian framework. We assessed the quality of
evidence contributing to each network estimate using the GRADE framework. This
study is registered with PROSPERO, number CRD42015016023.
FINDINGS:
We deemed 34 trials eligible, including 5260 participants
and 14 antidepressant treatments. The quality of evidence was rated as very low
in most comparisons. For efficacy, only fluoxetine was statistically
significantly more effective than placebo (standardised mean difference -0·51,
95% credible interval [CrI] -0·99 to -0·03). In terms of tolerability,
fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13
to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine,
venlafaxine, and duloxetine had more discontinuations due to adverse events
than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and
2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I2
values were 33·21% for efficacy and 0% for tolerability.
INTERPRETATION:
When considering the
risk-benefit profile of antidepressants in the acute treatment of major
depressive disorder, these drugs do not seem to offer a clear advantage for
children and adolescents. Fluoxetine is probably the best option to consider
when a pharmacological treatment is indicated.
_______________________________________________________________________
With the possible exception of fluoxetine (multiple brands),
the vast majority of antidepressants are ineffective, and some may even be
unsafe, for use in children and teens with MDD, new research shows.
"The only treatment that is evidence-based is
fluoxetine," lead researcher Andrea Cipriani, PhD, associate professor,
Department of Psychiatry, University of Oxford, Oxford, United Kingdom, told
Medscape Medical News.
However, Dr Cipriani stressed that this applies to children
with moderate to severe depression for whom psychotherapy or other
nonpharmacologic interventions have been tried without success or in situations
in which such interventions are unavailable.
"And it doesn't mean that if I have a patient who is
responding to escitalopram, that I should stop escitalopram and put that
patient on fluoxetine, because these are average data for an average
patient."
Dr Cipriani also stressed that the use of antidepressants in
children is "not cookbook medicine. Everything has to be individualized to
the specific patient."…
The primary outcome was mean overall change in depressive
symptoms and the proportion of patients who discontinued treatment because of
any adverse events. To assess change in depressive symptoms, the investigators
extracted a score from scales used in the studies. These scales included the
Children's Depression Rating Scale Revised, the Beck Depression Inventory, and
the Children's Depression Inventory…
Although the current study could not comprehensively assess
the risk for suicidality for all drugs, robust evidence suggested a
significantly increased risk for suicidality in young people given venlafaxine…
Although the data gathered by the FDA are not powered to
provide "clear answers," there is "a trend" of some drugs
being worse than others in terms of suicidality risk, said Dr Cipriani.
"The one-size-fits-all approach is misleading." The evidence suggests
that sertraline and fluoxetine are not associated with an increased risk for
suicidality, she added.
What is becoming clear from the research, said Dr Cipriani,
is that children with MDD significantly differ from adults with depression. In
children, the brain is still developing, and the clinical features of
depression in children are different from those in adults.
"In adults, mainly in the elderly, depression is a lot
about mood, while in young people, it's a lot about irritability and difficulty
with concentration," said Dr Cipriani. "We tend to call it all
depression and assume that the same drugs work for young people."
A main problem is lack of knowledge about the
pathophysiology of the disorder and identifying markers. "We don't have
hard outcomes to test a treatment."
A question plaguing trials of antidepressants -- among
adults as well as children -- is the high placebo response rate. According to
Dr Cipriani, 50% to 60% of patients respond to an antidepressant, and
approximately 40% respond to placebo, so the "added value" is roughly
10% to 15%.
The placebo response has increased during the years -- it
was approximately 20% in the 1980s -- probably because of methodologic
differences in trials. One example would be differences regarding the inclusion
of less severe patients, who tend to respond more to placebo.
"But in real practice, we don't use a placebo,"
said Dr Cipriani.
Childhood depression is "a huge problem" that is
growing, according to Dr Cipriani. Approximately 3% of children younger than 12
years have major depression, as do 6% of persons 13 to 18 years old…
In an accompanying editorial, Jon Jureidini, MD, a child
psychiatrist at the University of Adelaide and Women's and Children's Hospital,
in Adelaide, Australia, writes that the evidence for the use of antidepressants
in children is even weaker than the current study suggests.
"The data that the authors were working from was what
were available in published articles and clinical study reports," Dr
Jureidini told Medscape Medical News. "Unless you have access to
individual patient-level data, you can't be confident that what's in those
tables and spreadsheets that these authors had to work from is actually an
accurate representation of what was found."
From his own research, Dr Jureidini has learned that
"adverse events are underreported, and some outcome measures are
distorted."
One problem is that pharmaceutical companies carry out some
of the clinical trials; therefore, these companies "control the flow of
information," he said.
Another problem is that clinicians are often convinced that
these medicines do work, he added…
What is particularly bothersome, said Dr Jureidini, is that
although these drugs are not first-line therapy, "the idea seems to be
that you give the antidepressants anyway," he said. "That's just bad
medicine; if they're not good drugs, then you should avoid giving them."
An antidepressant in a child usually should be used only in
the inpatient setting, said Dr Jureidini.
He himself has not initiated antidepressant therapy in a
child more than once or twice in the past 5 years. However, it is not uncommon
for him to assume care for a child who is already receiving an antidepressant,
"and I wouldn't necessarily stop that."
In the absence of available psychotherapy, clinicians can
take other nondrug approaches to treat a child with depressive symptoms.
One is to look for a better explanation for the symptoms
than to just call it major depression. "Very often, symptoms are caused by
life circumstances, and sometimes those life circumstances can be addressed in
a way that resolves the symptoms."…
It might be a matter of helping the child to make sense of
what he or she is feeling. For example, he or she might still be grieving from
the loss of a beloved grandmother.
Dr Jureidini pointed out that depression usually lasts
weeks, not months.
Does he believe the use of antidepressants in children will
diminish significantly in response to this new study? "I hope so, but
probably not."
He sees 2 factors standing in the way of getting the message
across: pharmaceutical marketing, and key opinion leaders.
"In any community, particularly in North America, you
find senior, often academic child psychiatrists and others who are enthusiastic
prescribers of antidepressants and who will influence the prescribing pattern
of many other doctors."
Dr Jureidini anticipates that "prominent figures"
will "stand up and say either publicly or within their academic
communities that this paper is misleading, that antidepressants save lives, and
that we should all continue prescribing them."
http://www.medscape.org/viewarticle/865395
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