INDUSTRY SPONSORED CONSENSUS STATEMENTS?

Reflections on a BMJ editorial

Charles Medawar

P. Haddad, M Lejoyeux, A Young, Antidepressant discontinuation reactions Are preventable and simple to treat, Brit Med J, 11 April 1998, 316, 1105-1106. Fulltext  at http://www.bmj.com/cgi/content/full/316/7138/1105

 

This editorial makes a number of important observations, notably that many doctors are still unaware of the existence of antidepressant withdrawal reactions, and that symptoms are easily mistaken for a depressive relapse. But the authors also miss critical points, and protest too much that antidepressants are not drugs of dependence. Above all, they do not mention that, until recently, the American Psychiatric Association (APA) relied on a definition of "dependence" under which SSRI antidepressants could not possibly have escaped:

"The presence of a predictable physical abstinence symptoms following abrupt discontinuance of benzodiazepines is evidence of the development of physiological dependence … It has become apparent that physiological adaptation develops and discontinuance symptoms can appear after regular daily therapeutic dose administration… Since therapeutic prescribing is clearly not recreational abuse, the term dependence is preferred to addiction, and the abstinence syndrome is called a discontinuance syndrome." ¹

The Gospel has since been re-written (APA, 1994). It has been done by "consensus" (though naturally excluding consumers), and the effect is just slightly reminiscent of those old photos of Stalin which show his enemies disappearing one by one. Anyway, Haddad, Lejoyeux and Young emerge as born-again believers. The problem they see is that "patients need to be educated that antidepressants are non-addictive":

"Discontinuation symptoms do not in themselves indicate drug dependence. Dependence is a syndrome, and diagnosis requires several other features, such as tolerance, inability to control drug use, primacy of drug-taking behaviour, and continued use despite harmful consequences. Antidepressants are not associated with these other features and are not drugs of dependence. The common lay belief that antidepressants are addictive probably contributes to the significant under-treatment of depressive illness. It is important not to foster this belief inadvertently - one reason that "discontinuation reaction" is a better term that "withdrawal reaction".

Since 1994, the APA's redefinition has been rigidly focused on manifestations of "abuse",² (implicating the consumer, rather than the prescriber or drug). These authors defer to it though possibly, like other experts, they have concluded that this is a "necessary pretence", for they emphasise the point of it is to ensure that the people they think should be treated for "depression" actually are.

The authors of the editorial do not comment on the effect of this policy on risk management. The belief that there is no "dependence" continues to justify the failure to research the dependence risk, and the low standards of manufacturers' data sheet warnings. These are either non-existent or as understated as these things ever get - also a sad reflection on the orientation and standards of the Medicines Control Agency/Committee of Medicines and the European Medicines Evaluation Agency.

Possibly this indicates that the BMJ editorial also has some medico-legal significance. If and when antidepressants are ever acknowledged to be drugs of dependence, this is the surely one of the publications that will establish the "date of knowledge" for GPs - ie the date from which they "knew or ought to have known" of the risks. Beyond that date, lawyers for the plaintiffs would be increasingly less inclined to point to any deficiencies in the manufacturers' warnings and to the evidence of regulatory capture. The effect of this BMJ editorial might be to shift liability towards prescribers - especially any who failed to monitor their patients and basically dished up repeat prescriptions. It happened with many patients on benzodiazepines and, with all the emphasis on the need for long-term treatment with antidepressants, it could easily happen again.

The authors of the BMJ editorial overlook another real concern - that evidence of long-term antidepressant "efficacy" has come mainly from trials that discounted the possibility of withdrawal reactions. Thus every instance of withdrawal in these trials was counted as a relapse, and as evidence the drug was "working". Again there are worrying parallels with the benzodiazepines.

This editorial appears hard on the heels of several others on this subject by Haddad, Lejoyeux and Young. In particular, they contributed to five of the eight papers to emerge from a recent symposium on "Antidepressant Discontinuation Syndrome", also participating in a 7-man panel which produced two "Consensus Statements" - "A Hypothetical Definition" and "Possible Biological Mechanisms" of the SSRI Discontinuation Syndrome"

Both this "closed symposium" and some of the proceedings, recently published as a journal supplement, ³ were sponsored by Eli Lilly & Co, manufacturers of fluoxetine (Prozac). The symposium lasted one day, so it is not clear how two Consensus statements were prepared. No company personnel are identified as participants.

The symposium was held in Phoenix, Arizona, immediately before Christmas, 1996 - no mean destination for these three authors, who are based in Manchester, Paris and Newcastle. A letter for publication⁴ has been written to the BMJ to ask either, if no possible conflict of interest was declared, or if the Editor chose not to report it.

"Sometimes we may decide that our readers should know about a conflict of interest and we will then publish a note on the conflict - after consultation with authors or reviewers. To disclose a conflict of interest about a piece of work does not mean the work is worthless (otherwise there would be no point publishing it); but readers will want to consider that information along with many other factors in making their own judgements on the work."⁵

The emphasis in this editorial that "antidepressants are not drugs of dependence" very much accords with the main message from the regulatory agencies, also the organisers of the "Defeat Depression Campaign". Sponsored partly by the manufacturers of SSRIs, this was originally run by the Royal Colleges of Psychiatrists and General Practitioners (1992-1997); the Campaign is now run by an industry-funded, grass-roots patient organisation, called Depression Alliance.

1. American Psychiatric Association, 1990.

2. American Psychiatric Association, 1994.

3. Schatzberg et al, 1997

4.  The letter to the BMJ (sent in April 1998) was accepted, and page proofs sent etc. There followed endless delays and endless enquiries asking why. Eventually, in March 1999, the BMJ editor wrote: "I'm sorry that we haven't published your letter. This is my fault. I need to prepare a footnote to your letter, and I put it in a pile where it sank too far to the bottom. I will get ahead and produce the footnote and we will publish the letter soon."  Nothing had happened by November 1999 and probably nothing ever will. Ah well - CM

5. Smith R, Conflict of interest and the BMJ. http://194.216.217.166/guides/confli.htm at 9 April 1998

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