Antidepressant use and risk of adverse outcomes in older people: population based cohort study
Cite this as: BMJ 2011;343:d4551
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Antidepressant use in later life is an issue of high clinical and public health importance and remains poorly studied. Due to strict inclusion/exclusion criteria, older patients, especially those with relevant co-morbidities or concomitant medical therapy, are systematically excluded from the majority of randomised controlled antidepressant trials. Therefore, extrapolation of results from these studies to an older primary care population is difficult.
From a regulatory perspective, representativeness of patients included in drug approval trials relative to those who will be later treated with the drug is a matter of high interest. With the significant increase in the older population over the coming years, this group will have to be more specifically studied due to the high incidence of co- morbidity, co-medication, pharmacokinetic changes and increased risk of drug interactions. In this respect, the ICH (International Conference on Harmonisation) E7 guideline,(1) updated in 2008,(2) as well as the CHMP (Committee for Human Medicinal Products) guideline (EMEA/498920/2006)(3) are seminal approaches to foster an adequate consideration of older patients in approval trials.
The observational study by Coupland and colleagues(4) has considerable value. The authors analyse data from a large primary care database including older patients with a broad spectrum of co-morbidities and medical treatments. On the one hand, the study has the potential to provide findings of relevance for the real world situation. On the other hand, the results have to be interpreted with caution due to the inherent nature of the study design.(5) The study results challenge the long-held view that selective serotonin reuptake inhibitors (SSRIs) are superior to tricyclic antidepressants (TCAs) in terms of safety in this special population. This is further supported by a recent U.S. Food and Drug Administration (FDA) warning for citalopram indicating a dose-dependent QTc prolongation,(6) a problem of particular relevance for the elderly. However, it has also long been recognised that TCAs are problematic, especially with respect to their anticholinergic side effects. The choice of an appropriate antidepressant compound for an elderly patient is not a trivial task, requiring thorough consideration of the individual patient's situation, co-medication and co- morbidity. Drug treatment should be supplemented by psychological interventions, medical monitoring and objective explanation of the benefits and risks.
In summary, the study by Coupland and colleagues emphasises the need for inclusion of elderly patients in clinical studies as recommended by established regulatory guidelines. As the authors point out, the results of their observational study should inspire further research in this field. From the regulatory perspective, more data from randomised controlled trials in elderly patients is needed before specific clinical guidelines concerning antidepressant use in this population can be formulated.
1. ICH (International Conference on Harmonisation) Guidelines/Efficacy Guidelines/Work Products/E7 Studies in Support of Special Populations: Geriatrics. 24. June 1993. http://www.ich.org/products/guidelines/efficacy/article/efficacy- guidelines.html, accessed 12.09.2011
2. ICH (International Conference on Harmonisation) Final Concept Paper. E7 (R1): Studies in Support of Special Populations: Geriatrics (Revision of the ICH E7 Guideline). 23. October 2008. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Eff..., accessed 12.09.2011
3. CHMP (Committee for Human Medicinal Products) Adequacy of guidance on the elderly regarding medicinal products for human use. EMEA/498920/2006. http://www.emea.europa.eu
4. Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343: d4551.
5. Young SS, Karr A. Deming, data and observational studies. Significance 2011; 8: 116-120.
6. FDA U.S. Food and Drug Administration. Celexa (citalopram hydrobromide): Drug Safety Communication - Abnormal Heart Rhythms Associated With High Doses. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuma..., posted 24.08.2011
Competing interests: None declared
Working Group on Geriatric Medicines, Division Clinical Review, Sector Marketing Authorisation, Swis
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The study of Coupland et al. raises some interesting considerations regarding the treatment of depression in elderly patients. However, the inclusion of trazodone in the group of tricyclic drugs is interesting. The mechanism of action of trazodone remains somewhat unclear, however weak 5- HT reuptake inhibition and serotonin receptor antagonism have been described. This is in contrast to the marked neurotransmitter reuptake inhibition and muscarinic (amongst other) receptor antagonism associated with tricyclic antidepressants such as amitriptyline. Whilst the BNF lists trazodone as a "Tricyclic related antidepressant", it is neither chemically nor pharmacologically similar to these compounds and might be better placed with the "other" category of drugs in this study.
Dr Paul Deslandes PhD MRPharmS.
Competing interests: None declared
Cardiff and Vale University Health Board
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