Note: The main article [Cipriani et al] is available full text on line at the time I’m writing this, but I can’t tell for how long. If pediatric depression is of any interest to you, I would recommend saving it to your computer/desktop as that access might disappear.
Andrea Cipriani is an Oxford-based psychiatrist and author of numerous Systematic Reviews and Meta-analyses of psychiatric medications – many published by the Cochrane Collaboration. In short, he’s the real deal. I had an opportunity to see an advanced copy of this paper and my thought after reading it that this should be the new gold standard for this much discussed topic. The accompanying comment by Jon Jureidini is quite good, though I can’t locate a full text source on-line.
This has been such a conflicted issue from the earliest of days. Prozac® [fluoxetine] was approved for adolescent depression, then later Celexa®/Lexapro® were approved around the same time that the FDA appended the Black Box warning in 2004. No other SSRI/SNRI drugs have been approved for kids since then. This is a highly contentious issue ["this" being Are the drugs safe in kids? Are the drugs even effective in kids? Do they cause suicidality in some kids? suicides? homicides?].
by Andrea Cipriani, Xinyu Zhou, Cinzia Del Giovane, Sarah E Hetrick, Bin Qin, Craig Whittington, David Coghill, Yuqing Zhang, Philip Hazell, Stefan Leucht, Pim Cuijpers, Juncai Pu, David Cohen, Arun V Ravindran, Yiyun Liu, Kurt D Michael, Lining Yang, Lanxiang Liu, and Peng XieLancet. Published online June 8, 2016
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Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies’ websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents.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 predefi ned 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.
by Jon JureidiniLancet. Published online June 8, 2016
by Susan MayorBritish Medical Journal. Published 09 June 2016
The Pharmaceutical JournalBy Debbie Andalo9 JUN 2016Most antidepressants prescribed for children and adolescents with major and acute depressive disorders are ineffective, according to research published in The Lancet. Following a meta-analysis of data from 34 trials including 5,260 patients, researchers concluded that only fluoxetine was more effective than placebo in relieving symptoms in these young patients.
“Antidepressants in the acute treatment of major depressive disorder… do not seem to offer a clear advantage for children and adolescents,” say the researchers, led by Andrea Cipriani, department of psychiatry, University of Oxford, and Xinyu Zhou, department of neurology and psychiatry, the First Affiliated Hospital of Chongqing Medical University, China. “Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated,” they conclude…
But the researchers warn that the quality of the evidence was “very low” and poor study design makes it difficult to give a true and confident picture about the effectiveness and potential harm of these drugs for children and young people.“We cannot rule out the possibility that some unpublished studies are still missing or that published reports might overestimate the efficacy of treatments,” they say…
In an accompanying comment piece, Jon Jureidini, from the Critical and Ethical Mental Health research group at the Robinson Research Institute at the University of Adelaide, Australia, says the findings reinforce the need for independent researchers to be given access to individual patient level data in order to inform their research… Jureidini adds that the effect of misreporting is that antidepressants, possibly including fluoxetine, are likely to be more dangerous and less effective treatments than has been previously recognised. “There is little reason to think that any antidepressant is better than nothing for young people,” Jureidini concludes.
Katherine Delargy, deputy chief pharmacist at Barnet, Enfield and Haringey mental health NHS Trust, described the meta-analysis results as “important” but asks for more research to be carried out…
Steve Bazire, former chief pharmacist at Norfolk and Waveney Mental Healthcare Partnership NHS Trust, questions some of the reviewers’ conclusions: “The paper doesn’t necessarily show that antidepressants don’t work, just that we can’t prove or disprove it yet as the evidence was classed as very low quality.” He also queries the researchers’ suggestion that the first choice for adolescent depression should be “evidence-based psychotherapy”…
Bazire points out that previous research that directly compared drugs with cognitive behavioural therapy (CBT) showed that drug therapy is more effective. “So if antidepressants don’t work, neither does CBT,” he says. However, he acknowledges the dangers of antidepressant use and says they must be used with caution, starting with low doses and slowly increasing the dose to avoid any akathisia or heightened anxiety. “Patients must also be monitored for akathisia linked with suicide,” he adds.
‘Steve Bazire, former chief pharmacist at Norfolk and Waveney Mental Healthcare Partnership NHS Trust, questions some of the reviewers’ conclusions: “The paper doesn’t necessarily show that antidepressants don’t work, just that we can’t prove or disprove it yet as the evidence was classed as very low quality.” He also queries the researchers’ suggestion that the first choice for adolescent depression should be “evidence-based psychotherapy”…
Bazire points out that previous research that directly compared drugs with cognitive behavioural therapy (CBT) showed that drug therapy is more effective. “So if antidepressants don’t work, neither does CBT,” he says.’
These seem fair points. The studies were not designed, recruited, run, analyzed, selected, and packaged with the primary goal of informing clinicians. They were too often ghost managed as marketing devices.
So child and adolescent psychiatrists are operating to some extent in a vacuum when it comes to using these medications. I do not view these trials as representative enough of clinical practice to say that direct experience in clinical practice is without import. That these medications will not be used on that basis in some instances in practice.
It is a travesty that we have to operate in such a vacuum.
“I have no clue how to translate the fact that it’s overdiagnosed and overtreated in general into the management of a single case, so I have little to say about that. The cases I saw were underdiagnosed.”
http://1boringoldman.com/index.php/2014/01/09/adhd/
The Cochrane review on stimulants and ADHD might not change your view of those “n of 1” instances. I believe there is a valid parallel for how child and adolescent psychiatrists will approach this study in terms of clinical practice. The clinical experience matters, even in the face of this.
HOWEVER, the last line of that 2014 post is equally apt:
“we have the ability to know a lot more than they did, but that capability has been regularly mucked around with and I find that infuriating…”
I.e., just because the clinical experience matters does NOT mean the virtual absence of useful clinical trial information shouldn’t bother the begeebus out of us.
The way these trials have been allowed to be handled has done a disservice to us all.
That the situation is also sucky for the psychotherapy trials is also an important corollary.
Late to this important paper – but – how might Cipriani et al have reported this if also closely considering “Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports” BMJ 2016 Sharma et al http://www.bmj.com/content/352/bmj.i65 , and “Suicidal risk from TADS study was higher than it first appeared” Högberg et al, 2015 – http://content.iospress.com/articles/international-journal-of-risk-and-safety-in-medicine/jrs0645 both appearing after their data cut-off point. These clearly misreported data would, i suspect have tipped the balance clearly against SSRI/SNRI medications (overall simply very poor classes of chemicals the data consistently states) including fluoxetine.
Further, if adverse effects properly considered: eg “Adverse emotional and interpersonal effects reported by 1829 New Zealanders while taking antidepressants” http://www.psy-journal.com/article/S0165-1781(14)00083-3/abstract eg “Sexual Difficulties (62%) and Feeling Emotionally Numb (60%). Percentages for other effects included: Feeling Not Like Myself – 52%, Reduction In Positive Feelings – 42%, Caring Less About Others – 39%, Suicidality – 39% and Withdrawal Effects – 55%” – weighed against minimal, if ANY short term gain – is this an intervention we ought seriously be considering?
Jureidini critically emphasises this is NOT in any way saying “don’t treat” – simply don’t treat ineffectively, with unacceptable risks, and intolerable adverse effects short, medium and longer term. Please show us the solid, verifiable, openly accessible patient level data, not “expert opinion”, otherwise.
“Steve Bazire, former chief pharmacist at Norfolk and Waveney Mental Healthcare Partnership NHS Trust, questions some of the reviewers’ conclusions: “The paper doesn’t necessarily show that antidepressants don’t work, just that we can’t prove or disprove it yet…” some disclosures here, slide 2 – http://slideplayer.com/slide/800516/ – across the industry board, on advisory boards, conferences, talks etc. None mentioned in recent press comments.
None immediately apparent on the Psychotropic Drug Directory (now in its 23rd year) http://www.psychotropicdrugdirectory.com/
Nor I daresay on the VERY influential “Choice and Medication website (which) offers information about mental health conditions and the medications used in the mental health setting…” http://www.choiceandmedication.org/ – this is used by my LOCAL AUSTRALIAN GOVERNMENT mental health services for information for patients.
also here Choose Your Medication: Mental Health Application which gives essential information on over 21 mental health conditions (including depression, psychosis, dementia, anxiety, alcohol or substance misuse), http://www.chooseyourmedication.org/
? the modern, direct to the consumer, Key Opinion Leader?
Worth some digging and considering, it would seem.