Wednesday, August 3, 2016

Do antidepressants really work in children?

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.

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.
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Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents.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.
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.
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."

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