The Seroxat/Paxil story is far from over, in spite of the monumental admission this week by GlaxoSmithKline (GSK) that depressed adults treated with paroxetine might be six times more likely to exhibit suicidal behaviour than matched adults treated with placebo. There is a whole new chapter to be written, but it will take more than this to sort out the underlying problem: the management of drug health and safety issues is in some ways intensely poor.

This new, improved analysis of the risk of adult suicidality is mostly of data from clinical trials conducted 10 years ago or more. The main thing new is that this was the first independent analysis based on a blinded re-evaluation of the raw data. When the UK drug regulators, the MHRA, ran their ‘independent’ investigation of SSRI antidepressants, in 2003-4, they relied not on the raw data, but on summaries and analyses the manufacturers had prepared.

The limitations of this approach are evident from our on-going correspondence with the MHRA about the true nature of the so-called ‘placebo suicides’ reported in paroxetine-versus- placebo clinical trials. Briefly, both the MHRA and the European regulators (EMEA) accepted the company’s claim that, in these trials, three people on placebo committed suicide, compared with only one person on paroxetine. This was a key finding and central to the regulators’ enquiries, but an inherently implausible result. Moreover, it was based on brief summary evidence provided by a company then (and still) under investigation for suspected concealment of related evidence. Nevertheless, EMEA, the MHRA and its Expert Working Group saw no need to examine the raw data.

Those data are now in the public domain and they demonstrate that the three ‘placebo suicides’ were no such thing. Now it is up to the regulators to respond to our complaint that they have systematically deceived others as well as deluding themselves.

Meanwhile, the enormity of GSK’s recent admission has yet to sink in – as it was clearly never meant to do. How long will take for the media to recognise that the risk of suicidal behaviour in depressed adults on paroxetine – officially and emphatically denied for many years – may be twice as high as the risk for children? So far, the media have been thrown right off the scent, led to believe that this new finding is just a blip that mainly reflects the sensitivity of young adults – and therefore just a firmed-up result of a risk that was very tentatively trailed by the MHRA/EMEA a couple of years ago:

"There is no clear evidence of an increased risk of self-harm and suicidal thoughts in young adults of 18 years or over. However, given that individuals mature at different rates and that young adults are at a higher background risk of suicidal behaviour than older adults, as a precautionary measure young adults treated with SSRIs should be closely monitored." (Expert Working Group report, p. 119)

In fact, GlaxoSmithKline made no statement to prescribers in the UK, but left it to the MHRA and the Commission on Human Medicines – the parrot that rose from the ashes of the CSM. "What is the issue?" asks the Chairman of the CHM: "The MHRA has been made aware of a new analysis of Seroxat clinical trials which suggest that adults, particularly young adults with depressive illness, may be at increased risk of suicidal behaviour when treated with Seroxat." The thrust of the MHRA/CHM alert statement was that their 18-month ‘expert’, ‘independent’ investigation of SSRI antidepressants (2003/4) had been up to scratch:

"I am writing to inform you about the new analyses of paroxetine clinical trials that are being published by the manufacturer of Seroxat, GlaxoSmithKline …These new analyses examine the risk of suicidal behaviour in clinical trials in the adult population, and were conducted as part of a review by the US FDA. The new analyses highlight the importance of monitoring all patients treated with SSRIs for worsening of their symptoms or mood changes but do not alter the prescribing advice for SSRIs issued in December 2004 following the review by the CSM Expert Working Group on the Safety of SSRIs."

Here is a fine example of the Conspiracy of Goodwill at work – everyone united around a seemingly altruistic cause, but also for ulterior and self-interested motives. The underlying theme here is that that failure to treat depression is potentially far more dangerous than the drugs themselves might prove to be – and therefore that bad news about drug treatments for depression should so far as possible/credible be suppressed.

There is of course some truth in this, but it is much less than half of the whole. Yes, some people swear by paroxetine and other antidepressants and have found them hugely enabling and indispensable. On the other hand, the evidence clearly shows that two-thirds of all prescriptions are written for ‘mild’ depression – and only about 3% for ‘severe’ depression – yet there is no good evidence that antidepressants are effective when depression is ‘mild’. Most people prescribed antidepressants therefore have no expectation of benefit, but run considerable risks.

It only prolongs the agony – and compounds the impression of regulatory incompetence - that the MHRA/CHM/CSM and EMEA refuse to warn of this.

Charles Medawar
15 May 2006