Psychiatry
Major Depressive Disorder
Polypharmacy and Cognitive Impairment in Depression
Overview
In older patients with multiple medical problems, the use of a relatively long list of medications is often necessary. However, the use of multiple medications is also a major risk factor for adverse drug events – of which, a decline in cognitive performance and worsening functional status are distinct possibilities. The use of multiple medications is also a major risk factor for adherence problems and dosing and administration errors, which may worsen cognitive performance on any given day, week, or month. With respect to the treatment of major depressive disorder (MDD), there may be both favorable and unfavorable consequences of multiple antidepressant therapies. Given the heterogeneity of the etiology of depression, the use of >1 antidepressant might improve therapeutic outcomes by concurrently activating multiple neurological pathways with different mechanisms of action, but there is also the risk that this would increase the prevalence and severity of side effects. For these reasons, in the treatment of patients with MDD, the goal of “monotherapy to remission,” when feasible, has merit in that it can serve to simplify the medical regimen and/or emphasize the importance of optimizing the choice of antidepressant monotherapy before pursuing adjunctive or combination therapy.
Expert Commentary
Ira D. Glick, MD
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“Concomitant medicines have the potential to undermine the treatment in patients with MDD. One should go over the list medication-by-medication to see which ones, if any, are causing problems.”
Polypharmacy and untoward effects of medications clearly represent just one avenue to explore in the face of suspected mild cognitive impairment (MCI). Depression may be a final common pathway with many causes, and when it happens later in life for the first time, it is often due to underlying structural brain disease, including the early stages of dementia. Indeed, many treatment-seeking older adults with current episodes of MDD already have some degree of neurocognitive impairment. To be sure, there are many medical causes of depressive and cognitive symptoms in later life, including sleep disorders and relatively prevalent conditions such as thyroid dysfunction and deficiency of vitamins B12, D, and folate. All of these vitamin deficiencies can be associated with both mood and cognitive symptoms in older adults.
Nevertheless, in older depressed patients with MCI or suspected MCI, polypharmacy is an important consideration – and, potentially, a modifiable risk factor for cognitive impairment, along with others (eg, untreated depression, uncontrolled cardiovascular risk factors). The unfortunate truth is that patients often do not report drug-related symptoms to their physicians. The frequency of adverse drug events rises in proportion to the number of medications used, including some recognizable drug-specific phenomena but also nonspecific syndromes that may include decline in functional and cognitive status.
Steinman and Hanlon published a systematic approach for assessing and improving medication regimens, suggesting that, in addition to annual review of medications for older adults, declines in function and/or the onset or worsening of geriatric syndromes such as cognitive decline or falls should also precipitate medication review. Certain classes and combinations of medications are known to be more likely to contribute to cognitive deficits, and all current and over-the-counter medications should be reviewed.
Older patients tend to have a lot more medical problems and longer medication lists, so physicians have to be careful about concomitant medications. For instance, concomitant medicines have the potential to undermine the treatment in patients with MDD. One should go over the list medication-by-medication to see which ones, if any, are causing problems.
Anticholinergics stand out, in particular, as medications that patients are very commonly taking that can cause cognitive problems and problems with balance. Reviewing medication regimens and adjusting each dose as needed is important, and I try to give no more than the patient needs – and no less. I make careful diagnoses, disorder-by-disorder; and, then, treat only what they need. And I am very anti-polypharmacy.
When you think about people with chronic mood disorders who remain on ineffective treatments long after an adequate trial has lapsed, or remain on more than just 1 or 2 agents, and we start to get into the cumulative burden of tolerability and side effects and what’s iatrogenic and what’s not, that becomes a problem. Geriatric medicine internists pay a lot of attention to de-prescribing, particularly of anticholinergic medications, and other drugs on the American Geriatrics Society (AGS) Beers Criteria list.
References
American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015;63(11):2227-2246.
Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a clinical review. JAMA. 2014;312(23):2551-2561.
Steinman MA, Hanlon JT. Managing medications in clinically complex elders: “There’s got to be a happy medium.” JAMA. 2010;304(14):1592-1601.
