September 16, 2015

expert reaction to a report into the effectiveness of the antidepressant paroxetine in adolescents with major depression

Publishing in The BMJ a group of researchers has reanalysed the safety and effectiveness of two antidepressants when used in adolescents, reporting that neither was clinically or statistically better than a placebo.

Dr Michael Bloomfield, Clinical Lecturer in Psychiatry, MRC Clinical Sciences Centre and University College London, said:

“This new study re-analyses data from a controversial trial that has been the subject of a number of legal cases. The authors report that contrary to previously published research, the study measuring the effects of an antidepressant called paroxetine did not find it to be statistically better than placebo. It should be pointed out that the authors have themselves been witnesses in these legal cases and they do declare this potential conflict of interest in the paper.

“Despite this new analysis, there is growing and consistent evidence that, along with most other illnesses, the earlier patients are treated, the better they do. Paroxetine is not currently recommended for the treatment of depression in young people by widely used guidelines. There are other antidepressants that have been shown to be safe and effective when used in young people, and these should be offered to young people when their symptoms are severe enough, along with expert psychiatric care.

“Depression, whilst common, can be a potentially fatal illness. Suicide and other psychiatric illnesses are the commonest causes of death in young people. It is therefore extremely important that we understand how to provide better treatments in order to prevent these tragedies.

“For some time, there has been evidence that antidepressants are associated with a short-term increased risk of suicidal thinking in young people. During this period young people may need increased follow-up to monitor this. From a scientific perspective it can be very difficult teasing out the increased risk of suicide directly caused by a depression from say the potential risk of suicidal thinking that may be associated with a particular treatment.  However, of particular concern, is the finding that decreased patterns of antidepressant use in response to these fears has been associated with an increase in the suicide rate.

“Despite the awful effects of psychiatric illnesses in young people, funding for Child and Adolescent Psychiatric services is challenging. We must not forget that there is currently a national shortage of in-patient beds for vulnerable young people. Likewise, medical research spending on understanding mental illnesses and how to improve their treatments is far less than for other “physical health” conditions. At the same time, the majority of drug companies are pulling out of psychiatric research. Therefore, we must properly invest in good quality psychiatric clinical care and academic research to improve outcomes for young people with mental illnesses. Anyone concerned about their own or a loved one’s mental health should speak to their GP or psychiatrist. No one should stop taking an antidepressant without discussing this with their doctor first.”

Prof. Celso Arango, President-Elect of the European College of Neuropsychopharmacology (ECNP) and Professor of Psychiatry, Gregorio Maranon General University Hospital, Madrid, said

“I think that these results are more informative of the quality of the methodology used than the efficacy of the antidepressant in question, paroxetine. Having said that, we have to follow the evidence available and so far the evidence is that only fluoxetine clearly shows a clear beneficial balance of efficacy and safety in adolescents with moderate and severe major depression.”

Prof. Guy Goodwin, President of the European College of Neuropsychopharmacology (ECNP), said:

“The original description of this data concluded that Paroxetine is generally well tolerated and effective for major depression in adolescents. This re-analysis concludes that it isn’t.  Neither concrete interpretation can be correct because in this trial placebo response rates were over 60% making definitive detection of drug efficacy unlikely with this sample size. The efficacy data appear to be identical in both analyses. So the argument here is over whether the cup is half full or half empty.

“Without a definitive measure of efficacy it is difficult to contextualize the reported side effects in a clear statement of risk/benefit for paroxetine in young people. Favourable data from an independent clinical trial is available for a similar serotonergic drug, fluoxetine, especially in combination with a psychological treatment (http://www.ncbi.nlm.nih.gov/pubmed/17909125).

“Innovative research to improve the management of depression in young people should be an important priority for public funding”.

Dr Sarah Bailey, Senior Lecturer, Department of Pharmacy and Psychopharmacology, University of Bath, said:

“This paper reports a reanalysis of a randomised controlled trial for the use of paroxetine in treating adolescents with depression, originally reported in 2001. This is one of a handful of such papers that have attempted to reanalyse clinical trial data. By going back to the original study protocol, following the methods set down and accessing original trial data, this reanalysis shows that paroxetine is not as effective, and carries a greater risk of adverse effects, than was reported at the time.

“The protocol for a clinical trial is important because it sets out the objectives of a study and your planned analysis before you gather any data so it should be free from any bias. This reanalysis highlights that some of the planned analyses were not carried out at all and some were carried out incorrectly. This paper raises important questions about the conduct of science research: how do we ensure that all clinical trial data is readily accessible for independent analyses? How do we remove misleading publications from the record?​ This paper demonstrates the importance of access to all of the data gathered for clinical trials and the importance of independent statistical analyses to interrogate data. But there are huge challenges in how we handle “big data” – these large data sets from clinical trials should be made available but doing that is complex – how do you store information, search data, share data and ensure information privacy for medical data. These are challenges faced by all scientists in an era where we are encouraged to make all our data open access.

“In terms of the take home message from this reanalysis that paroxetine is not safe in adolescent depression, this is not a particular advance in knowledge. Shortly after the trial “Study 329” was reported it was recognized as flawed. However, the original publication has never been retracted.

“Since the original publication of Study 329 in 2001 there have been a number of randomised controlled trials looking at the drug treatment and psychological therapies for the treatment of adolescent depression. Indeed, concerns about the safety of paroxetine meant that it was not even tested in some of these trials. Based on these trials (see below for details) and other evidence, the NICE guidance does not recommend the use of paroxetine in adolescent depression.

“The NICE guidance for the treatment of depression in children and young people puts forward a stepped-care model of depression that provides a framework where psychological therapies are introduced and if the depression is diagnosed as moderate or severe then fluoxetine ( a selective serotonin reuptake inhibitor SSRI) is the recommended treatment. All drug treatments carry a risk of side effects – fluoxetine is the only SSRI for which the benefits to the adolescent depressed patient outweigh the risks. What this study does highlight is the lack of effective treatments for adolescent depression and the need for new, better drug treatments.”

Further information from Dr Sarah Bailey:

Treatment of Adolescent Depression Study (TADS)

Silva S, Petrycki S, et al. Treatment for Adolescents with Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. Treatment for Adolescent Depression Study (TADS) randomized controlled trial. J Am Med Assoc. 2004;292:807–820

Adolescent Depression Antidepressant and Psychotherapy Trial (ADAPT)

Goodyer I, Dubicka B, Wilkinson P, et al. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behavior therapy in adolescents with major depression: Randomised controlled trial. Br Med J. 2007;335:106–111.

Treatment of SSRI-Resistant Depression in Adolescents study (TORDIA)

Brent DA, Emslie GJ, Clarke GN, et al. Switching to venlafaxine or another SSRI with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. J Am Med Assoc. 2008;299:901–913.

Sequenced Treatment Alternatives to Relieve Depression study (STAR*D)  March J,

Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs.2009;23:627–647

‘Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence’ by Le Noury et al. published in The BMJ on Wednesday 16th September. 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/?s=antidepressant&cat

Declared interests

Dr Michael Bloomfield:  I am a member of the Royal College of Psychiatrists, a trainee member of the British Association of Psychopharmacology and a young member of the European College of Neuropsychopharmacology. I conduct research funded by the Medical Research Council, the National Institute of Health Research and the British Medical Association.  I work in medical research at the Medical Research Council and University College London.  I work clinically in the National Health Service. I have no other financial interests to declare.

Prof. Celso Arango: I have advised Servier and Lundbeck on methodology for clinical trials with antidepressants in paediatric population

Prof. Guy Goodwin: I have advised Lundbeck and Servier on the development and use of antidepressants. I have never advised GSK on the use of paroxetine.

Dr Sarah Bailey: I am a Council member for British Association for Psychopharmacology, member of the British Pharmacological Society’s Education and Training Committee, and member of the British Pharmacological Society’s Animal Welfare and In Vivo Pharmacology Group