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Rapid Responses: Rapid Responses published:
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Tryptophan, serotonin and treatment adherence
- Dietmar Fuchs (30 June 2006)
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Adherence to a prescription might be a specific treatment
- Georg Ivanovas (4 July 2006)
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Extrapolation of meta-analysis findings.
- Albert Tan (5 July 2006)
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'healthy behaviour effect' may be a socio-economic gradient in outcome
- Martin White, Jean Adams, Research Fellow (8 July 2006)
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A different view of the 'effect' of adherence to dosing regimens for trial placebos
- John Urquhart, MD, FRCPE, FRSE (8 July 2006)
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Is the placebo effect always in the right direction?
- CK Connolly (13 July 2006)
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Intergrating biomedical & Social Science research collaboratively may yield a better answer
- Sam W Mhlongo, Medunsa 0204, South Africa (13 July 2006)
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The healthy adherer-effect.
- Boris LG van Wijk, Bors LG van Wijk, Diane .M.A. van Wieren – de Wijer, John Urquhart, Eibert.R. Heerdink, Anthonius de Boer, Olaf H. Klungel. (10 November 2006)
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Dietmar Fuchs, Biocentre at Medical University Innsbruck, Austria
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Dr.S.H. Simpson et al. evaluated the relation between adherence to drug therapy and placebo and mortality. For participants with good adherence to therapy, the risk of mortality was about half of that of participants with poor adherence. From the meta-analysis data, drug/placebo adherence increases mortality by approximately half. Authors conclude that good adherence to drug therapy is associated with positive health outcomes. Surprisingly this was true in the verum and the placebo groups. Indeed, adherence to drug therapy may be a surrogate marker for overall healthy behaviour. It could also be linked with tumour biology and its interaction with the immune system: activation of tryptophan degrading enzyme indoleamine (2,3)-dioxygenase (IDO) is induced during inflammation and immune activation (1). And lower free tryptophan concentrations in serum/plasma was found to be associated with reduced survival expectation in patients with HIV infection, with cardiovascular risk and also in various forms of cancer, e.g., colorectal cancer and malignant melanoma (2 -4). Reduced tryptophan availability influences production of neurotransmitter 5-hydroxy tryptamine (serotonin), which is also involved in memory and cognitive function (5). Higher tryptophan and serotonin levels may allow patients better adhere to the instructions by the physician and, vice versa, better adherence to treatment may serve as an indirect marker of a less disturbed tryptophan metabolism and serotonin biosynthesis. Dietmar Fuchs
1. Schroecksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta 2006;364: 82-90. 2. Fuchs D, Moeller AA, Reibnegger G, Werner ER, Werner-Felmayer G, Dierich MP, et al. Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection. Immunol Lett 1991;28:207-12. 3. Brandacher G, Perathoner A, Ladurner R, Schneeberger, S, Obrist P, Winkler C, et al. Prognostic value of Indoleamine 2,3- dioxygenase expression in colorectal cancer: impact on tumor-infiltrating T-cells. Clin Cancer Res 2006;12:1144-51. 4. Weinlich G, Murr C, Richardsen L, Winkler C, Ueberall F, Fuchs D. Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients. Dermatology (in press) 5. Mitchell ES, Neumaier JF. 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacol Ther 2005;108:320-33. Competing interests: None declared |
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Georg Ivanovas, physician private surgery
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In their article Simpson et al. believe that the adherer effect “may be a surrogate marker for overall healthy behaviour” (1). But to regard this effect as a result of the general life style is only one possible explanation. The adherence to a prescription might be an effective therapeutic intervention on its own. The so-called Ordnungstherapie (therapy of order) (2) has always maintained that the introduction of a clear principles into the life of a patient is beneficial. As modern life dissolves all natural pacemakers and as chronic diseases are mostly characterized by the lack of rhythms and time structure (3), it might be possible that the regular intake of a drug is a specific treatment as such and not only a secondary phenomenon. (1) Simpson SH, Eurich DT, Majumdar SR, Padwal R, Tsuyuki RT, Varney J, Johnson JA: A meta-analysis of the association between adherence to drug therapy and mortality, BMJ 2006; 333:15 (2) Brüggemann W: Ordnungstherapie im Sinne einer Lebensordnung, in: Brüggemann W (ed): Kneipptherapie, Springer, Berlin, 1980, pp 222 - 228 (3) Hildebrandt G, Moser M, Lehofer M: Chronobiologie und Chronomedizin, Hippokrates, Stuttgart, 1998, p. 33 Competing interests: None declared |
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Albert Tan, 5th year medical student University of Dundee, DD1 4HN
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In the meta-analysis by Simpson et al (1), it showed that there was positive association between good adherence to drug therapy with positive health outcomes. Having read the online inclusion criteria for their meta- analysis, I am perplexed that only studies related to HIV infection, diabetes and cardiovascular diseases were included into their meta- analysis. Does this imply that the findings from the meta-analysis could be extrapolated to adherence of psychiatric or paediatric drug therapies as well? Perhaps a more specific concluding statement directed just to the studies included could have been made. 1)Simpson SH, Eurich DT, Majumdar SR, Padwal R, Tsuyuki RT, Varney J, Johnson JA: A meta-analysis of the association between adherence to drug therapy and mortality, BMJ 2006; 333:15 Competing interests: None declared |
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Martin White, Professor of Public Health Newcastle University, NE2 4HH, Jean Adams, Research Fellow
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Simpson et al explain the effect of drug placebos on mortality in terms of a ‘healthy behaviour effect’.[1] Whilst this is a plausible and testable hypothesis, it provides a simplistic and incomplete explanation for a profound effect. There are many reasons why some people have more healthy behaviour patterns than others, one of the most powerful being socio-economic position. Almost universally, poorer or more disadvantaged people have less healthy behaviour patterns than the more affluent or advantaged, whether measured by social class, educational attainment, income or the type of area in which people live.[2-4] The reasons for these strong social gradients are not yet clear, but may involve variables such as access to resources,[5] general and specific knowledge,[6 7] people’s sense of control over their lives[8] and their future orientation (the extent to which they are willing to forego present benefits in exchange for potentially greater benefits in the future).[5 9] It is likely that the ‘healthy behaviour effect’[1] is substantially, if not entirely, explained by socio-economic position. Understanding the causal pathway between socio-economic position and response to health interventions is important because it offers opportunities for understanding and tackling social inequalities in health and avoiding further iatrogenic socio-economic inequalities in outcome.[10 11] Thus, understanding that poorer groups are less likely to take their drugs - and why - could lead to different ways of delivering drug interventions to different (social) groups. A one-size-fits-all approach to drug prescribing, health education, screening or indeed any health intervention can lead to a widening of social inequalities in outcome.[12- 14] We need to understand at what points such adverse socio-economic outcome gradients occur and develop ways to tackle them. Trials of drugs and other health technologies, such as those reviewed in Simpson et al’s meta-analysis,[1] often collect socio-economic data in order to control for confounding. Such data can be used in secondary analyses to identify whether socio-economic position is driving differential outcomes, such as those observed in this study. Martin White (martin.white@ncl.ac.uk) and Jean Adams (j.m.adams@ncl.ac.uk) References 1. Simpson SH, Eurich DT, Majumdar SR, Padwal R, Tsuyuki RT, Varney J, et al. A meta-analysis of the association between adherence to drug therapy and mortality. BMJ 2006;333:15. 2. Townsend P, Davidson N. Inequalities in health. The Black Report. London: Penguin Books, 1982. 3. Townsend P, Phillimore P, Beattie A. Health and deprivation: Inequality and the North. London: Croom Helm, 1988. 4. Acheson D. Independent Inquiry into Inequalities in Health. London: HMSO, 1998. 5. Charlton B, White M. Living on the margin: A salutogenic model for socio-economic differentials in health. Public Health 1995;109(4):235-43. 6. Wardle J, McCaffery K, Nadel M, Atkin W. Socioeconomic differences in cancer screening participation: comparing cognitive and psychosocial explanations. Social Science & Medicine 2004;58(2):249-261. 7. Goldman DP, Smith JP. Can patient self-management help explain the SES health gradient? Proceedings of the National Academy of Science 2002;99(16):10929-10934. 8. Marmot MG. Contributions of job control and other risk factors to social variations in coronary heart disease incidence. The Lancet 1997;350:235-239. 9. Fuchs V. Time preference and health: an exploratory study. Cambridge, Mass: National Bureau of Economic Research, 1980. 10. Tugwell P, de Savigny D, Hawker G, Robinson V. Applying clinical epidemiological methods to health equity: the equity effectiveness loop. BMJ 2006;332:358-361. 11. Victora C, Vaughan J, Barros F, Silva A, Tomasi E. Explaining trends in inequalities: evidence from Brazilian child health studies. The Lancet 2000;356:1093-1098. 12. Scott A, Shiell A, King M. Is general practitioner decision making associated with patient socio-economic status? Social Science and Medicine 1996;42(1):35-46. 13. McKevitt C, Coshall C, Tilling K, Wolfe C. Are there inequalities in the provision of stroke care? Analysis of an inner city stroke register. Journal of Epidemiology and Community Health 2004;58(S2):A21. 14. Middleton E, Baker D. Comparison of social distribution of immunisation with measles, mumps, and rubella vaccine, England, 1991-2001. British Medical Journal 2003;326:854. Competing interests: None declared |
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John Urquhart, MD, FRCPE, FRSE, Chief Scientist, AARDEX Ltd; Emeritus Professor of Pharmacoepidemiology, Maastricht University; 975 Hamilton Ave, Palo Alto, CA 94301 USA
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Sir: The meta-analysis by Simpson et al. (1) shows a strong inverse association between adherence with placebo regimens and mortality in 21 trials. The conclusion reached by the review, and the associated commentary by Chewning (2), was that the explanation is to be found in a presumed (but to my knowledge never really studied with reliable methods) association between adherence with drug dosing regimens and with various healthy lifestyle factors, e.g., exercise, diets high in fruits & vegetables, non-smoking. Almost all of these trials involved the use of non-trial medications (and maybe all, for it is unclear from the papers what the extent of use of non-trial medicines actually was). Tight coupling between compliance with trial agents (either active or placebo) and compliance with non-trial medicines could create the appearance of an ‘effect’ of variable compliance with the trial's placebo. A non-trial medicine, by definition, is one deemed too important to the patient's care to be discontinued for the purposes of improving trial sensitivity. Poor adherence to the prescribed dosing regimens for non-trial medicines can thus reasonably be expected to be harmful, the more so with more severe disease. Electronically compiled dosing histories of concomitantly prescribed medicines support the conclusion of a strong association between adherence with one and all co-prescribed medicines (3), but more robust analysis of this association is needed. Neither of the first two big primary prevention trials of lipid- modifying agents found any relation between adherence with placebo and lipid changes (4). These were studies of patients who, at enrolment, had elevated lipid levels but were free of overt disease. Though some were, in the course of these multiyear trials, to contract overt coronary heart disease and/or other conditions, for which non-trial medicines would have been prescribed, the prevalence of non-trial medicines use would have been low. This difference is reflected in the 8.4-fold higher mortality in the Coronary Drug Project Trial (CDPT) than in the aforementioned primary prevention trials (4). All patients enrolled into CDPT had had a prior myocardial infarction, ~half of whom at the start of the trial were taking non-trial medicines indicative of a diagnosis of congestive heart failure (4). Alas, no attempt was made to capture evolving changes in prescribed non-trial medicines in the course of that study. Today, it is clear that evolving histories of drug prescribing/dispensing are, when complete, an economical source of good information on the evolution of each patient’s diseases and their respective severity -- a cornerstone of the “Dutch school” of pharmacoepidemiology in the past 2 decades and a useful window onto changing health status of patients over time (5). Also, today electronically compiled drug dosing histories can provide much more reliable and complete information on patients’ actual exposure to prescribed drugs than was possible when most of the studies in the meta- analysis were run (6,7). Thus, the usual conclusion is ‘more work has to be done’, especially on the links between adherence to (a) trial agents, (b) non-trial drugs, (c) lifestyle factors, before leaping to one view or the other. Perhaps both (b) and (c) play a role, but how strong is each? References: 1. Simpson SH, Eurich DT, Majumdar SR, Padwal R, Tsuyuki RT, Varney J, Johnson JA. A meta-analysis of the association between adherence to drug therapy and mortality, BMJ 2006; 333:15-20. 2. Chewning B. The healthy adherer and the placebo effect. BMJ 2006;333:18-19 3.. Cramer J, Vachon L, Desforges C, Sussman NM. Dose frequency and dose interval compliance with multiple antiepileptic medications during a controlled clinical trial. Epilepsia 1995; 36: 1111-7. 4. Urquhart J. Patient compliance as an explanatory variable in four selected cardiovascular trials. In: Patient Compliance in Medical Practice and Clinical Trials. Eds Cramer JA, Spilker B. New York: Raven Press, 1991, 301-322. 5. Leufkens HG, Urquhart J. Automated record linkage in The Netherlands. Chapter 20 in: Pharmacoepidemiology, 4th Ed. Strom B., ed. Chichester (UK): John Wiley, 2005, 311-22. 6, Liu H, Golin CE, Miller LG, Hays RD, Beck CK, Sanandaij S, Christian J, Maldonado T, Duran D, Kaplan A, Wenger NS. A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Intern Med 2001; 134: 968-77. 7. Vrijens B, Tousset E, Rode R, Bertz R, Mayer S, Urquhart J. Successful projection of the time-course of drug concentration in plasma during a one -year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models. J Clin Pharmacol 2005; 45: 461-7. Competing interests: I am a partner in AARDEX Ltd, pioneer developer of electronic means for compiling drug dosing histories in ambulatory patients. |
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CK Connolly, retired physician Aldbrough St John, Richmond, North Yorkshire DL11 7TP
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The authors are to be congratulated on their wide ranging review and their interesting discussion which was enhanced by the commentary of Betty Chewning. As observed difference is similar in the active, (specific effect plus placebo),and the placebo groups the difference must be in the placebo response, but there may be alternatives to suggestion that this reflects a generally healthy lifestyle. The placebo reponse is generally asssumed to be positive. This is almost certainly always true when the patient comes to the doctor with symptomatic disease. However there is possibility that that it is much weakened, or even adverse when the roles are reversed and the doctor comes to the patient and suggests primary prevention or treatment of asymptomatic disorders. This has been called the commoveamus effect in a recent informal article in Clinical Medicine ( Coegemus. Everyone a patient? Beware the Commoveamus effect! Clinical Medicine 2006 5 665:666). It may be that the poor compliers are those whose healthy state,which is not the simple antithesis of diseaese, is critically dependent on the belief that disease is absent and that the intervention has destroyed this perception, and so their good health. If so the difference betweeen the two groups should be greater the less the intervention is related to symptomatic disease. If the hypothesis has any basis then it has important implications for selection of subjects for such interventions This might be particularly relevant to those who have rarely if ever previously attended ther doctor. Competing interests: None declared |
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Sam W Mhlongo, Professor of Family Medicine University of Limpopo, Medunsa Campus,, Medunsa 0204, South Africa
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Scot H. Simpson et al in their article under the heading 'A Meta- analysis of the association between adherence to drug therapy and mortality' conclude that 'Good adherence to drug therapy is associated with positive health outcomes'(BMJ, Vol. 333, 15-18). In response to this statement, a cynic might feel justified in stating that this is music to pharmaceutical companies! A major problem with this meta-analysis is that virtually all the papers cited had as their bedrock biomedical science. To an extent, this is understandable since to date there is little or no collaboration between biomedicine and social science when randomised drug trials are carried out. This type of research remains the unchallenged domain of biomedical science. By far, the majority of authors of published papers on compliance are social scientists - Nicky Britten, David Armstrong, Myfawny Morgan, etc. It is noted that a large number of the references on compliance in this article relied extensively on social or behavioral sciences - it could not be otherwise. Among this large number of social scientists quoted is P. Conrad. Amongst the conclusions in his study of compliance or non-compliance, Conrad stated that "higher compliance rates are associated with physicians giving explicit and appropriate instructions, more clear information, and more and better feedback." (1) Conrad's study also showed that social class or educational status were irrelevant factors in compliance with medical regimens. It is clear from an analysis of the designs and conclusions of papers on compliance with a social science perspective that mortality is not considered. Equally, the biomedical scientists fail to seriously address patient behaviours during randomised trials. In these disparate approaches of biomedicine and social science, it is easy for biomedical scientists to conclude that good adherence with drug regimens is associated with positive health outcomes. This necessarily implores the following question: Why? In virtually all well designed studies, the populations that are studied are usually highly motivated and so are the researchers. Such populations consequently receive 'better' clinical care. This is called the "Hawthorne effect"(2). Ref. (1)Peter Conrad: The Meaning of Medications: Another look at Compliance. (Social Science Medicine Vol.20, No.1, 1985 (2)Robert Clarke & Peter Croft: Critical Reading for the Reflective Practitioner: Butterworth/Heinemann 1998 Competing interests: None declared |
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Boris LG van Wijk, PhD--candidate Utrecht, 3584CA, Bors LG van Wijk, Diane .M.A. van Wieren – de Wijer, John Urquhart, Eibert.R. Heerdink, Anthonius de Boer, Olaf H. Klungel.
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Reply to: Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, Varney J, et al. A meta-analysis of the association between adherence to drug therapy and mortality. Bmj 2006;333(7557):15. The healthy adherer-effect. BLG van Wijk1, B.M.A. van Wieren – de Wijer1, J Urquhart2, E.R. Heerdink1, A de Boer1, O.H. Klungel1. 1Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University 2Chief Scientist, AARDEX Ltd; Emeritus Professor of Pharmacoepidemiology, Maastricht University; Sir, Simpson and colleagues demonstrate in their thoughtful meta-analysis that patients adherent to medication regimens have better health outcomes than those who are non-adherent, regardless of whether the drug consumed was a placebo or contained an active ingredient. [1] The authors suggest that patients more adherent to medication intake also have a more overall healthy behaviour. To verify this suggestion, we requested data from the PHARMO-database, a Dutch prescription database, currently covering more than 2,000,000 patients. We identified a sub sample of patients taking blood pressure lowering medication between 1991 and 2003 for which detailed information on lifestyle was available. Pharmacy records can be used to assess adherence to medication in an easy and non-invasive way, although generally overestimating actual drug intake.[2] We calculated the refill rate for antihypertensive drugs in the year preceding the date for which lifestyle information was available. In a number of age and gender adjusted logistic regression models, we analysed the association between various indicators of healthy behaviour that are known to be associated with cardiovascular outcomes [3] and suboptimal adherence. A total of 4,857 patients showed an average refill rate of 93.8% (+/- 11.4), while 445 patients (9.2%) had a refill rate below 80%. Infrequent exercising (OR 1.67 [95% CI: 1.02-2.70]) was associated with non-adherence. A trend towards worse adherence was seen for patients who did not follow a low salt diet (OR 1.29 [95% CI: 0.70-2.33). A body mass index above 30 kg/m2 was not associated with non-adherence (OR 0.97 [95%CI: 0.75-1.26). Compared to patients who consumed of 1 or 2 units of alcohol a day, complete abstinence (OR 1.83 [95%CI: 0.98-3.39]) and more frequent drinking (OR 1.73 95% CI: 1.01- 2.93) were associated with non-adherence. Patients who stopped smoking were as adherent as patients who never smoked (OR 0.99 [95% CI: 0.79-1.24]) in contrast to smokers, who were significantly more often non-adherent (OR 1.36 [95% CI: 1.02-1.80]). Although we probably underestimated the prevalence of non-adherence by using pharmacy records, thereby inevitably misclassifying non-adherent patients, introducing bias towards the null, the results at least suggest that some indicators of healthy behaviour could indeed be associated with adequate medication refilling. Next to non-adherence with other medications, as suggested by Urquhart [4], part of the positive association between adherence and outcomes observed by Simpson and colleagues [1] may be explained by the absence of information on indicators of healthy behaviour. 1. Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, Varney J, Johnson JA. A meta-analysis of the association between adherence to drug therapy and mortality. Bmj. 2006 Jul 1;333(7557):15. 2. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005 Aug 4;353(5):487-97. 3 1: Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52. 4 Urquhart J. A different view of the 'effect' of adherence to dosing regimens for trial placebos. Posted on: http://bmj.bmjjournals.com/cgi/eletters/333/7557/15#137359 Competing interests: None declared |
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