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Rapid Responses: Rapid Responses published:
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Randomised controlled trials - a flawed approach to behavioural research
- Kath Checkland (19 March 2001)
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Extent of use of highly anticholinergic antidepressants as sedatives in the elderly
- Sudip Sikdar (29 March 2001)
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Cognitive toxicity of antidepressants
- David B Menkes (7 April 2001)
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Responses from the authors
- M E C van Eijk, J Avorn, A J Porsius, A de Boer (24 May 2001)
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Kath Checkland, GP Marple Cottage Surgery, Stockport
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I was disappointed to find that the BMJ continues to publish articles describing randomised controlled trials of interventions to change human behaviour. We seem to have reached a position in which the statement “systematic reviews of rigourous studies provide the best evidence of the effectiveness of different strategies for promoting behavioural change.” [1] is accepted without question. We have been mesmerized by the aura of spurious scientific respectability surrounding the initials “RCT”. The phrase “hierarchy of evidence” is trotted out on all occasions, with little or no thought for the true nature and purpose of an RCT. In the natural sciences, experimenters can be confident that one sample of calcium carbonate will respond in exactly the same way as any other when treated in the same way. Chemists therefore only need to perform their experiments on one sample. When investigating the effects of drugs on the human body, we cannot make the same assumption. The human body is complex, and so in order to gain some idea of what the average effect of a drug will be, we carry out the same test on large numbers of people. In order to minimize unwanted effects, we make the trial randomized and, if at all possible, double blind as well. The results give us statistical information about the probable effects of a particular drug. We can accept such results because we can assume that if the same person were given the same drug on several occasions, their body will respond in the same way. The body cannot choose how to respond to a drug. When investigating human behaviour, as van Eijk et. al. set out to do, we can make no such assumption. Human beings can choose how to respond to an intervention. An educational input which catches my imagination on one occasion, may not do so on another occasion if I am bored, tired or emotionally distressed. The effects of an intervention can only be assumed to hold true on one occasion, with one set of individuals. Randomly assigning people to different groups will not result in control for all other factors, as it is impossible to know how what influences an individuals preferred learning style. All this is important, because large amounts of time and money are spent on studies such as this. I agree that it is vital that we try and understand the process of professional behaviour change. If we are to obtain useful information we must stop subjecting large groups of individuals to interventions and assuming that the results obtained will hold true for totally different individuals – or even the same individuals at a different point in time, and start asking people about their responses to interventions. Only by understanding how people learn and decide how to behave through well-conducted qualitative studies will we begin to make progress. 1. Bero, L., et al., Getting research findings into practice. Closing the gap between research and practice: an overview of systematic reviews of interventions to promote the implementation of research findings. British Medical Journal, 1998. 317: p. 465. |
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Sudip Sikdar, specialist Registrar Mossley hill hospital, Liverpool
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Dear Sir, I read van Eijk et al's1 article with interest. One of the commonest reasons for prescribing tricyclic antidepressants in the elderly in general practice in the UK is for their sedative effects. Since the problems of dependence with benzodiazepines many GPs are reluctant to prescribe that group of drugs to the elderly who complain of sleep problems. The common belief is that antidepressants are safer. Unfortunately, the antidepressants that are used for their sedative effects are highly anticholinergic and also have alpha blocking effects making them dangerous for the elderly . To review the extent of this type of prescribing, I examined computer records of two large multi-partner GP practices in the north of Liverpool. There was a total of 120 patients who were receiving tricyclic antidepressants as sedatives. The commonest prescribed drug was amitryptiline(in 92 cases), followed by Dothiepin(in the rest). Both the drugs were prescribed in 50 mg dose. The average age of the patients was 82 years, women outnumbered men by 3 to 1. 70% of the patients have been continuously taking the drugs on repeat prescription for an average of 5 years. The patients were also taking on an average four other classes of medication. None of the patients reported any current depressive symptoms or any past history of depression. All of them agreed that they were given the tablet for sleep problems. None of the patients were ready to even consider coming off the tablets. Sleep problems in the elderly is common and to some extent a symptom of ageing. Instead of prescribing tricyclic antidepressants, GPs should first try and explain the physiological change in sleep architecture in old age and promote good sleep hygiene techniques. Even when medication is prescribed, it should be reviewed. Long term use of antidepressants(even in low doses) in the elderly has serious consequences(i.e., confusion, falls, constipation, hypotension, tardive dyskinesia). Since most elderly patients are on more than one medication, co-prescribing with tricyclic antidepressants also increases the risk of adverse drug interaction. Reference 1. Eijk van ME, Avorn J, Porsius JA, Boer A. reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing. BMJ 2001; 7287: 654- 657(17 March). Conflict of interest : none |
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David B Menkes, Liaison Psychiatrist, Dunedin Hospital Dunedin, New Zealand
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van Eijk and colleagues refer to extensive literature regarding antidepressant prescription and its problems in the elderly (1). It is unfortunate that their classification of antidepressants into "highly" and "less" anticholinergic categories appears flawed. Radioligand data provide clear evidence that antidepressants vary enormously in their ability to antagonize the muscarinic receptor in human brain, providing the likely mechanism for memory dysfunction and delirium (2). The data indicate that classical tricyclics are uniformly more potent that other antidepressants, and it is thus surprising that the authors consider several tricyclics, including trimipramine, to be "less anticholinergic", while the tetracyclic maprotiline, with one-tenth the affinity, is included in the "highly anticholinergic" category. van Eijk and colleagues' results show that risky prescribing practices are modifiable. It would be of interest to determine the clinical impact of such a strategy, either in reducing antimuscarinic burden, as can be measured in peripheral blood (3), or by decreasing the rate or severity of cognitive dysfunction. Unfortunately, the latter may be particularly difficult to demonstrate, because cognitive impairment in the elderly is often multifactorial, and multiple drugs, not just antidepressants, may contribute to antimuscarinic toxicity (3-5). References 1. van Eijk ME, Avorn J, Porsius JA, Boer A. reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing. BMJ 2001;322:654-7. (17 March) 2. Richelson E, Nelson A. Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. Journal of Pharmacology & Experimental Therapeutics 1984;230:94-102. 3. Tune LE. Serum anticholinergic activity levels and delirium in the elderly. Seminars in Clinical Neuropsychiatry 2000;5:149-53. 4. Moore AR, O'Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs & Aging 1999;15:15-28. 5. Gray SL, Lai KV, Larson EB. Drug-induced cognition disorders in the elderly: incidence, prevention and management. Drug Safety 1999;21:101 -22. Conflict of interest : none |
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M E C van Eijk, researcher DGV Dutch Institute for Rational Drug Use, J Avorn, A J Porsius, A de Boer
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re Dr Checkland's comments: We cannot agree with Dr Checkland that there is no place for randomised controlled trials in studies of human behaviour; this assertion would deny the utility of entire branches of the social sciences! To the contrary, although human actions are certainly more complex than simple chemical reactions, there is more than ample evidence that well conducted studies can yield important findings about the effects of behavioural interventions. Thousands of papers in psychology and related disciplines confirm this. In fact, it is irresponsible not to conduct such methodologically sound studies of behavioural interventions in medicine, since this is the most effective way of learning what works and what doesn't. We do, however, agree that qualitative analysis also has an important role to play. In our opinion it can add to our knowledge on human behaviour, next to quantitative studies. re Dr Sikdar's comments: Dr. Sikdar is correct that improving sleep hygiene is a more effective and far safer way to improve sleep than daily doses of 50 mg amitryptiline in the very old, which as he points out are more likely to induce a host of CNS side effects. Audits such as the one he performed are a valuable tool in assessing prescribing quality, and should be conducted far more often. re Dr Menkes' comments: We have chosen for a classification in highly and less anticholinergic antidepressants which is in accordance with other information GPs in the Netherlands receive. We realised that there is evidence available in literature to support another classification. However, as this was primarily a study on human behaviour we did not want to dilute the effect of our intervention by giving conflicting information. Next to the intervention described in this article, we also sent a questionnaire to all 60 plus users of antidepressants. We experimented dichotomising the data on antidepressant use in several ways, including receptor affinity, dosage and regimen. This did not increase the correlations between antidepressant use and complaints, not even of dry mouth. We agree that evaluation of the clinical impact of our strategy is of great importance as well. M.E.C. van Eijk, Martine@van-eyk.net J. Avorn, JAVORN@partners.org A.J. Porsius, A.J.Porsius@pharm.uu.nl A. de Boer, A.deBoer@pharm.uu.nl |
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