Friday, 29 January 2016

Antidepressants double risk of aggression & suicide for young, according to meta analysis of data

Children and adolescents have a doubled risk of aggression and suicide when taking one of the five most commonly prescribed antidepressants, according to findings of a study published in The BMJ today. (The following is taken from the email sent to APRIL by the BMJ.)

However, the true risk for all associated serious harms, such as deaths, aggression, akathisia and suicidal thoughts and attempts, remains unknown for children, adolescents and adults, say experts.
This is because of the poor design of clinical trials that assess these antidepressants, and the misreporting of findings in published articles.

Selective serotonin reuptake inhibitors antidepressants (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed drugs for depression.
A team of researchers from Denmark carried out a systematic review and meta-analysis of 68 clinical study reports of 70 trials with 18,526 patients to examine use of antidepressants and associated serious harms.
These included deaths, suicidal thoughts and attempts as well as aggression and akathisia, a form of restlessness that may increase suicide and violence.

They examined double blind placebo controlled trials that contained patient narratives or individual patient listings of associated harms.

Harms associated with antidepressants are often not included in published trial reports, explain the authors. This is why they analysed clinical study reports, prepared by pharmaceutical companies for market authorisation, and summary trial reports, both of which usually include more information.
In adults, they found no significant associations between antidepressants and suicide and aggression. However, a novel finding showed there was a doubling of risk for aggression and suicides in children and adolescents.

This study has shown limitations in trials, not only in design, but also in reporting of clinical study reports, which may have lead to "serious under-estimation of the harms," write the authors.
They compared the results from the clinical study reports with data from individual patient listings or narratives of adverse effects. This revealed misclassification of deaths and suicidal events in people taking antidepressants.

For example, four deaths were misreported by a pharmaceutical company, in all cases favouring the antidepressant, and more than half of the suicide attempts and suicidal ideation, for example, were coded as "emotional lability" or "worsening of depression."
In the Eli Lilly summary trial reports, almost all deaths were noted, but suicidal attempts were missing in 90% of instances, and information on other outcomes was incomplete. These were "even more unreliable than we previously suspected," write the authors.

Clinical study reports for antidepressants duloxetine, fluoxetine, paroxetine, sertraline and venlafaxine were obtained from regulatory agencies in the UK and Europe. Summary trial reports for duloxetine and fluoxetine were taken from the drug company Eli Lilly's website.

However, clinical study reports could not be obtained for all trials and all antidepressants, and individual listings of adverse outcomes for all patients were available for only 32 trials.
"The true risk for serious harms is still unknown [because] the low incidence of these rare events, and the poor design and reporting of the trials, makes it difficult to get accurate effect estimates," they explain.

They recommend "minimal use of antidepressants in children, adolescents, and young adults, as the serious harms seem to be greater, and as their effect seems to be below what is clinically relevant," and suggest alternative treatments such as exercise or psychotherapy.
They also call for the need to identify "hidden information in clinical study reports to form a more accurate view of the benefits and harms of drugs."

In an accompanying editorial, Joanna Moncrieff from University College London, agrees that "regulators and the public need access to more comprehensive and reliable data", and that clinical study reports "are likely to underestimate the extent of drug related harms."
Over half the clinical study reports had no individual patient listings and "this begs the question of how many more adverse events would have been revealed if [these] were available for all trials, and raises concerns why this information is allowed to be withheld."
Link to research
Link to editorial


Additional information about antidepressant trial data added to this blog February 2017

Restoring Study 329 - The study that disproved anti-depressants’ efficacy


A major reanalysis of the infamous clinical trial, Study 329, has shown Paroxetine (also known as Paxil or Seroxat), one of the most commonly prescribed antidepressants, to be unsafe and no more effective than a placebo.


This new assessment directly contradicts the results of the clinical trial that claimed Seroxat to be “generally well tolerated and effective”, which was sponsored by and ghostwritten for GlaxoSmithKline, despite using the same original data.


The latest paper was published under the restoring invisible and abandoned trials (RIAT) initiative, in order to re-evaluate any conclusions drawn from evidence that had previously been hidden from public view.


Published in 2001, Study 329 generated a high level of controversy from patients and doctors after lawsuits were filed stating the side-effects were much more serious than those documented in the clinical trials.


Restoring Study 329, showed Paroxetine (Seroxat or Paxil) to have no significant reduction of depressive symptoms more than a placebo or previous anti-depressants, and gave users a higher chance of psychiatric side effects.


The original study came under intense scrutiny following revelations that it was ghost written by GSK authors and not those named on the study, and the primary data was not made publically available.


The findings of Study 329, originally published in 2001, was the first double blind patient study to report the efficacy of anti-depressants on adolescents.


It has allowed Seroxat to gain widespread approval by the healthcare industry, becoming the most widely prescribed anti-depressant in the US, with over 14 billion dolllars worth of sales between 1997 and 2004.


Following a decade of public and legal pressure, GSK finally released the original data to the public, making its reanalysis possible.


These devastating results overturning the original paper may come as no surprise to many who have already suffered loss and harm from the drug. In  2012 GSK were successfully sued $3 billion for fraudulently promoting Paroxetine to the public, and hiding key data in its study, such as reclassifying suicidal acts so that they would not count in the final analysis.


To this day however, GSK remain silent on the issue and continue to promote the drug to its customers, without any attempt to acknowledge the restoration of the study.


A personal note to our readers:


As we reveal these facts about Seroxat, we do not wish to condemn all use of anti-depressants nor encourage the immediate withdrawal from the medication.  It is important to obtain advice from responsible health professionals who can help to plan any reduction in drugs that may cause dependence. It is also important to inform those close to you when you plan to start, reduce or stop taking antidepressants.


We wish to highlight the potential dangers and risks of Paroxetine and similar medication, and let readers understand that medical information to support the drug can be unreliable or biased.


Both starting and coming off anti-depressants is a serious undertaking and we strongly advise that users seek professional medical help as well as inform either close friends or family when doing so, as it can be a tough process which needs careful monitoring and support.


We recommend considering talking therapy and CBT to those who have access to these services, as these have been shown to provide beneficial reductions of depression and anxiety with fewer and less serious side effects.




Further Reading


Article on Study 329

British Medical Journal Analysis of Study 329

David Healy’s website on the controversy of Study 329

Restored Study 329


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