"Late-life depression is both under-recognised and undertreated, and the impact of medical comorbidity may mask depressive symptoms.”
A. M. Yohannes & R. C. Baldwin, “Medical comorbidities in late-life depression”¹. 

La polymédication: “…une  pratique compliquée chez la personne âgée, elle entraîne une augmentation des effets secondaires, des interactions médicamenteuses et un manque d’observance thérapeutique” [Polypharmacy: a complicated matter for elderly persons, involving an increase in side effects, drug interactions and lack of adherence to therapy]. J.Mendlewicz with P.Oswald, “Dépression et Vieillissement”². 

Comorbidity is the presence in one person of two or more illnesses, each of which requires treatment. Polypharmacy is the concurrent prescribing and dispensing of several medicines to such a patient. 

The link

Depression in elderly persons is commonly accompanied by one or more comorbidities. The connection between comorbidity and polypharmacy is that the former is virtually certain to lead to the latter. Different illnesses require different medicines, but polypharmacy - although generally unavoidable - can involve six distinct problems: 

1. Harmful side effects as a result of interaction between medicines for the same condition (e.g. the concurrent administration of two different antidepressants)
2. Harmful side effects as a result of interaction between different medicines for one or more comorbidities
3. Over-prescribing causing adverse reactions and/or non-compliance by patients 
4. Under-prescribing by doctors trying to avoid Problems 1,2 & 3, or for other  reasons which may include cost containment
5. Patients receiving separate and uncoordinated prescriptions of different medicines for comorbidities from more than one GP and/or consultant physician, followed by uncoordinated pharmacy dispensing (possibly by different pharmacies) 6. Harmful side effects when patients decide to add non-prescription medicines to their prescribed regimen without taking professional advice.

The main comorbidities of elderly depression

A variety of reviews describe different comorbidities as frequently prevalent with elderly depression, the following being widely cited:

• Coronary heart disease
• Cerebrovascular disease and stroke
• Parkinson’s Disease
• Diabetes
• Pancreatic and some other cancers
• Thyroid anomalies
• Dementia, Alzheimer’s Disease
• Insomnia
• Musculoskeletal pain 

The fact that depression can be either the cause or the consequence of other illnesses complicates both diagnosis and choice of treatment. The recognition of comorbidities may involve consultants in different disciplines with different priorities who are prescribing a range of possibly incompatible medicines. Moreover, for elderly patients with comorbidities, there can be a tendency for doctors to assign the highest priority not to depression but to the ‘other’ disease(s). The physician’s explicit or unspoken notion that a certain level of depression ‘is natural at your age’ can further aggravate the sense of neglect surrounding elderly depression when compared with its comorbidities.

How does depression interact with comorbid conditions?

This is not entirely clear and would benefit from more targeted research. In broad terms, a review of studies has concluded that elderly depressed patients have higher rates of medical comorbidity than younger depressed patients and than elderly patients who are not depressed;  that comorbidity has an adverse effect on the response to antidepressant medication; and that it is probably a material cause of worsening both the duration and the prognosis for elderly depression³. In short, depression should be regarded as a risk factor for  many forms of chronic disease in ageing populations.

While these conclusions may appear to be no more than commonsense, their implications for the handling of elderly depression are far from obvious, because individual co-morbidities interact with depression in different ways, and the number of comorbid conditions tends to increase with advancing age and will present more and more complex challenges to diagnosis and treatment.  For example, analysis of  a sample of 1,801 American patients  aged 60+ with major depression or dysthymia revealed the most common comorbidities  as hypertension at 58% of the sample, chronic pain 57%, arthritis 56%, and sensory deficit 55%⁴.  Yet there is little evidence to suggest that elderly depression is interactive with hypertension, whereas its interaction with chronic pain/arthritis is well recognised. 

To what extent is depression cause or consequence of comorbid conditions?

More profound knowledge of the nature of interaction between depression and its comorbidities could be an important guide to therapy, but evidence is patchy and has probably until now had little impact on medical practice.

There are exceptions. In the U.S.,  about 20% of coronary heart disease patients are  reckoned to be at risk of ‘significant symptoms of depression’ and “patients with baseline depression were at 81% higher risk for coronary heart disease than patients without depression” (Ref.1). Similarly, a review of the interaction between diabetes and depression has shown that “patients with major depressive disorder (MDD) have a much higher subsequent relative risk of developing type 2 diabetes….(and) patients with both type 1 and type 2 have a higher relative risk of developing mood disorders” than the general population⁵.

From comorbidity to polypharmacy

Today, polypharmacy is a fact of everyday life among a significant proportion of elderly persons. A 2006 survey of patterns of medication use in the U.S.  showed that 28% of non-institutionalised adults aged 65+ had used five or more prescription drugs in the preceding week, and that polypharmacy was on a steadily rising trend since 2000⁶. The impact of advancing age is strikingly illustrated by evidence from Sweden where 58% of men and 61% of women aged 90+ were found to be regularly using four or more prescription medicines⁷.

In hospitalised patients, the prevalence of polypharmacy is probably even higher. An Italian study has analysed the total number of drugs prescribed to patients on leaving acute care hospitals: 1,976 were given up to six different drugs, while 489 received seven or more. Among those given up to 6 drugs, 26% had depression as one of their diagnosed conditions; this rose to 42% among those who had prescriptions for 7 or more drugs. Overall, in the ‘7 or more drugs’ group, three-quarters were aged 65+. The authors comment that “age per se does not carry a higher risk of polypharmacy, while age-related polypathology* does” [*comorbidity]. More specifically, they conclude that “depressive symptoms are significantly associated with polypharmacy even after having excluded antidepressants and anxiolytics from the computation.”⁸.

Antidepressant treatment and drug interactions

Antidepressant medication is an essential feature of early and continued treatment, and most patients without comorbidities will respond  positively to one or other antidepressant drug. That is true for elderly as well as younger patients, although adverse reactions are more prevalent in  the elderly unless the choice and dosage of medication is carefully adjusted to individual needs. 

The focal point, however, is the fact that elderly patients with depression are more prone to single or multiple comorbidities than younger patients.  They are therefore more likely to receive prescriptions for a variety of drugs in addition to antidepressants and to experience the problems associated with polypharmacy.

The British National Formulary devotes pages of its Appendix I to closely printed lists of interactions between different types of antidepressants with other drugs and with one another. Even for the SSRIs [Selective Serotonin Reuptake Inhibitors], currently the most widely used group of antidepressants and highly regarded for their safety, the BNF lists interactions with 28 other categories of drugs of which 16 are annotated as ‘potentially hazardous’ with the recommendation that combined administration “should be avoided (or only undertaken with caution and appropriate monitoring”⁹. 

While the Formulary contains special advice about the use of SSRIs in children and adolescents, there are no similar cautions about risks in the treatment of elderly depressed patients. This might be explained by the fact that official commentary is based mainly on the results of clinical trials from which the elderly are either excluded altogether or excluded if they have comorbidities. While this will produce evidence about the side effects of individual antidepressants (which may well be unrelated to age), the interactive impact of comorbidity and polypharmacy on antidepressant treatment of the elderly tends to escape scrutiny and attention.

Where do we go from here?

Randomised clinical trials measuring the effect of antidepressants on elderly patients with comorbidities are generally regarded as too complex and too costly in practice if they are to produce conclusive, comparable and reproducible results.

A more practicable alternative is a carefully targeted, evidence-based approach to the management of elderly depression in both primary care and in institutions.  Formal disease management has proved capable of improving the conduct and outcome of care for cardiovascular and respiratory diseases in ‘real life’. In our rapidly ageing society, it is high time for the complexities of elderly depression to be added to the roster of disease management. There is no shortage of practical evidence that such management can be applied to depression, for example in the form of ‘collaborative care’ (organised team work) as well as by way of a more integrated approach to the combination of medication with psychotherapy which can be particularly effective with elderly patients. 

New approaches to the management of elderly depression will be the theme of the next article in this series.

Related articles:
Elderly Depression: Its Prevalence, Causes and Implications for Society 1/5
Elderly Depression: The age factor in depression 2/5
Elderly Depression: are doctors and patients failing to connect? 3/5
Elderly Depression : New approaches to the management of elderly depression 5/5