Dr Tim Kendall
Deputy Director, Royal College of Psychiatrists Research Unit
In December 2003, in an unprecedented move, the Department of Health agency responsible for ensuring that medicines meet appropriate standards of safety and effectiveness (MHRA), released data regarding the risks and benefits of newer antidepressants used to treat depression in children and young people.
The information published on the MHRA's website included both previously published and never before published data obtained directly from the manufacturers of the antidepressant drugs.
These data were collected after earlier work had raised concerns about the safety of paroxetine (Seroxat) and venlafaxine (Efexor, Efexor XL) in children and young people with depression.
Based on their review of the data, the MHRA concluded that all of the newer antidepressant drugs, other than fluoxetine (Prozac), carried serious risks that outweighed any benefits.
The MHRA, therefore gave warning of the potential that these drugs could increase the risk of suicide-related behaviour (rather than decreasing it - as would be expected of an antidepressant) when using these drugs in the treatment of depression in childhood and adolescence.
Dr Tim Kendall
The MHRA informed all doctors that the use of SSRIs (except fluoxetine) was now "contraindicated" in this context. However, this was not the commonly held view in the published literature with recent studies in particular suggesting that these drugs were beneficial and well tolerated with no serious side effects.
At this time, we* had been commissioned by the National Institute for Clinical Excellence (NICE) to produce national guidelines for the whole of the NHS on the treatment of depression in children and young people.
We produce most of the NICE guidelines in mental health, each one taking about 2 years to produce and giving advice on the treatments which have the best evidence for their effectiveness.
It is important to note that up until this point in our work for NICE, all our guidelines (and all other NICE guidelines as far as we are aware) have been based upon an in-depth assessment of the PUBLISHED evidence.
So, when the MHRA verdict on the SSRIs became public, we became aware that the MHRA had a total of 11 trials, of which we had only seen 5, since only 5 had been published.
We had already written to all relevant drug companies, asking them to furnish us with ALL relevant published and unpublished trials of the treatment of children and young people with depression - no unpublished trials were forthcoming.
Because of the inconsistency between the MHRA's findings and the published literature, several members of our guideline committee, decided to compare and contrast the published data with the unpublished data.
This work was designed as an experiment to test out what the difference might (or might not) be if, in producing a guideline, we had access to the unpublished as well as the published literature.
The results of this work** were published in The Lancet, a British-based medical journal.
The authors of the Lancet article concluded that the published evidence was more favourable than the unpublished evidence, and most importantly that it was only when all evidence was examined that it was clear that the risks (particularly the increased risk of suicidal behaviour and thinking) outweighed the benefits.
We also found evidence to suggest that at least one of the drug companies who had undertaken trials of an SSRI in the treatment of childhood and adolescent depression had withheld publication of trial data on the grounds that it suggested that the trial data suggested that the drug was ineffective in treating depression in this age group.
The arguably profound implications of this study are relevant, not just for the treatment of children and adolescents who are depressed, but for the whole project of evidence-based medicine, which depends upon the honesty and transparency of all people who undertake clinical research to publish ALL the findings of research and not just selective and positive findings as a means of encouraging the use of a drug.
The above article is background to a Lancet paper on the benefits and safety of SSRIs in children.
*The National Collaborating Centre for Mental Health (NCCMH) on behalf of the National Institute for Clinical Excellence
**Whittington C, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. The Lancet, 24 April 2004; Volume 363: Number 9418, 1341-45.
The Lancet editors also penned a hard-hitting and extremely critical editorial calling for new regulation of drug companies in the light of an increasing weight of evidence (including our review) suggesting that drug companies were not publishing evidence that showed their own drugs may be ineffective and/or harmful to patients ("Depressing Research" in the same edition of the Lancet).
Tim Kendall (Co-Director, NCCMH; Deputy Director, Royal College of Psychiatrists Research Unit; Medical Director and Consultant Psychiatrist, Sheffield Care Trust)
Craig Whittington (Senior Systematic Reviewer, NCCMH; Honorary Senior Lecturer, UCL sub-department of clinical and health psychology)