Coleg Meddygaeth Prifysgol Cymru

University of Wales College of Medicine

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Adran Meddygaeth Seicolegol / Department of Psychological Medicine
Adran Cymru y Gogledd / North Wales Department
Pennaeth Adran / Head of Department
Yr Athro /Professor Michael J. Owen
Dr. D. Healy (Cyfarwyddwr)


Dr June Raine, Director of
Post-Licensing Division, MCA
Market Towers, 1 Nine Elms Lane
LONDON SW8 5NQ 4 April 2001

Dear Dr Raine,            


Many thanks for your letter of the 27th March 2001.

As regards the data relating to the Hindmarch study, you will no doubt know better than I that there should be many sets of data including a study report by the sponsors, the raw data from the actual study which will often involve assessments by the investigators themselves as well as by the subjects and further data which may include specific comments on the study by company monitors etc. All the above appears to be fairly standard for many of these studies with the resulting documentation coming in three or four distinctly different bundles and often running to over 100 pages worth of material. A four page synopsis certainly does not tally with the material that I have reviewed of this particular study.

When with you before Christmas, I mentioned the Saletu study. There has been a further publication of this study Saletu B & Grumberger (1998), Drug Profiling By Computered Electro Encephalography and Brain Maps: With special consideration of Sertraline and its psychometric effects. Journal of Clinical Psychiatry 49, 8(Suppl), 59-71. Between the two published versions it is now clear that there is a dose-dependent agitation produced by Sertraline and the suggestion made to me by Professor Evans at the MCA meeting that the reported difficulties on the drug may not refer to individual subjects taking Sertraline appears not to be the case. The set of side-effects that I outlined in the meeting do refer to distinct individuals.

There is a further study published with Paroxetine (Warrington et al), Warrington SJ, Dana-Haeri J, Sinclair AJ (1989). Cardiovascular and Psychomotor Effects of Repeated Doses of Paroxetine: A comparison with Amitriptyline and Placebo in healthy men. Acta Psychiatrica Scandinavia 80, (Suppl 350), 42-44. , Referring to the drop out of several healthy volunteers while taking Paroxetine this study, the authors state that antidepressants are poorly tolerated in healthy volunteers.

The problem this poses to both you and me is this. As far as I am aware no similar statements could ever have been made about the benzodiazepines. The wholesale switch then from prescribing benzodiazepines for minor nervous problems to prescribing SSRIs for minor nervous problems is one that is fraught with difficulties. The relative risk a drug is of course not some absolute value, it is proportionate to the risk posed by the condition being treated for. Where more serious depressions are being treated the poor tolerance of the compound is less of a problem. Where the population being treated is at minimal if any risks of suicide however such problems need necessarily to be seen in a completely different light.

At this stage I have reviewed the preponderance of healthy volunteer studies conducted by both Pfizer and SmithKline prior to submission of their initial licensing applications. At present our discussions are restricted by legal orders to the few phrases about the Hindmarch study that appear in my deposition, the published Saletu and Warrington studies as well as our own study here in North Wales. I can assure you however that the rest of the data I have reviewed are broadly consistent with the position that can be deduced from the published literature.

It may also be worth noting that in the File on Four programme which ran on BBC Radio 4 last year a General Practitioner stated that many GPs recognise the problem and will do something like prescribe concomitant benzodiazepines to minimise the problem during the early phrases of treatment with an SSRI and not a tricyclic. It is also the case that consultant psychiatrists up and own the country from the very early 1920s on have been doing something similar. It seems to me to be an extraordinary situation to have a problem that is so widely recognised on the one side with people instituting prophylactic treatment to avoid the problem or prescribing antidotes to minimise the problem without there being any warning in the data sheets.

In two weeks time I am due to give a public lecture in North America on just these issues. It will probably contain statements that I have consulted with the MCA on the issue of studies which have been described as epidemiological studies and no one from the MCA has challenged characterisation of these studies as not epidemiological studies.

The other point that my talk will include is the fact that a variety of people working for Pfizer including Roger Lane and Christine Blumhardt as well as Ian Hudson and David Wheadon working for SmithKline and Charles Beasley working for Lilly as well as independent experts retained by these companies such as John Mann and Daniel Casey have all testified in the course of the last year that since the controversy with SSRIs and suicide blew up that no research designed to explore the link between SSRIs and suicide has been instituted. The current position as I understand it is that one study was designed in conjunction with the FDA, this was a re-challenge study, but it never took place.

For a variety of other factors aside from the interest in the issue of SSRIs and suicide, this lecture in Toronto is likely to receive media coverage. I think there is a real chance that the issue of SSRIs and suicidality will become increasingly salient in weeks to come. I will post you the transcript of the talk in a few weeks time. I plan to make this available widely.

Yours sincerely

David Healy MD FRCPsych
Director, North Wales Department of Psychological Medicine
Uned Hergest, Ysbyty Gwynedd, Bangor, Gwynedd LL27 2PW
Ffn: (01248) 384452 Ffacs: (01248) 371397
Hergest Unit, Gwynedd Hospital, Bangor, Gwynedd LL27 2PW
Tel: (01248) 384452 Fax: (01248) 311397

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