Antidepressant use and risk of adverse outcomes in older people: population based cohort studyBMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d4551 (Published 02 August 2011) 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
1. ICH (International Conference on Harmonisation)
Guidelines/Efficacy Guidelines/Work Products/E7 Studies in Support of
Special Populations: Geriatrics. 24. June 1993.
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.
3. CHMP (Committee for Human Medicinal Products) Adequacy of guidance
on the elderly regarding medicinal products for human use.
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.
Competing interests: No competing interests
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: No competing interests