This longitudinal cohort study demonstrated an association between the combined use of CNS medications, especially at high doses, and an increased risk of clinically important cognitive decline. This relationship was detected in a large sample of healthy, community dwelling older persons even after controlling for a number of potentially confounding factors that also could have affected central nervous system function. Furthermore, both short and long duration of CNS medication use were associated with a 5 point decline on the 3MS, a clinically important cognitive decline. These findings were consistent with a study examining the risk of these CNS medication use variables on another common geriatric syndrome, recurrent falls.47
These findings also were consistent with the findings of studies of single classes of CNS-active medications that demonstrated an association between medication use and cognitive decline.2, 3, 6, 7, 9, 10
For example, Pomaro et al, and Hanlon et al, found that higher doses of benzodiazepines were associated with cognitive decline while lower doses were not.7, 10
Marcantonio et al, found that higher doses of certain opioid analgesics, specifically meperidine, were associated with delirium 9
while another study showed that immediate release opioids were more likely to be associated with cognitive decline than delayed release opioids.48
A few studies have attributed decline in cognitive function to antidepressant and antipsychotic use because of their anticholinergic and sedative properties.2, 5
The analyses in the current study encompassed the (combined) use of all of these classes of CNS medications.
This study has several noteworthy implications. First, these findings should not be interpreted as suggesting that the treatment of pain or psychiatric symptoms should be avoided because of the risk of cognitive impairment, especially since these conditions are often under-treated. A study by Morrison et al., showed that the risk of delirium was more pronounced in those with severe pain as opposed to the use of opioids.49
Similarly, the use of tricyclic antidepressants for depression has been associated with positive, negative, and a lack of effects on cognitive function.50, 51
It is conceivable that different agents within the same major class of medications (e.g., antidepressants) may affect cognitive function differently. However, it is interesting to note in the current study that both SSRI use and tricyclic antidepressant use demonstrated similar risks to cognitive function. Ultimately, the practical implications of this study suggest that clinicians should use the lowest possible combined doses of CNS-active medications, particularly when treating concurrent pain and psychiatric conditions, in order to minimize the risk of cognitive decline. Further research may be able to identify specific combined dosing thresholds beyond which the incidence of adverse effects on cognitive function dramatically and unacceptably increases. As a second noteworthy implication, these findings reiterate the possibility that a reversible
component to cognitive decline may exist in the presence of excessive dosing of CNS-active medications. Further research may elucidate this possibility. Third, the question of whether CNS-active medication use in healthy older adults is associated with incident cognitive impairment has not been satisfactorily answered, and other larger studies are needed to explore this.
This study has several potential limitations. First, the measure of cognitive function, the 3MS, was not as sensitive to change as a full battery of neuropsychological tests (e.g., visual reproduction test, trails B, verbal fluency, word list recall) would be.24, 52, 53
However, psychometric testing of the 3MS has demonstrated its reliability between raters and its ability to approximate in studies estimates of the actual incidence of mild cognitive impairment separately from dementia.20
Secondly, medication use information was limited to that collected at three points in time. Nonetheless, one of the strengths of medication data collection in the Health ABC study is that it is based upon participants’ actual medication use rather than a clinician’s record of medications prescribed to participants or pharmacy dispensing. A third limitation is that given the low incidence of cognitive impairment (as measured by the dichotomous 3MS measure), the power to detect any association with CNS medication use was limited. For example, post-hoc calculations revealed that this study had 9.1% power to detect the magnitude of the association between higher (> 3 SDD) doses of CNS medications and cognitive impairment. However, it is important to note that the hazard ratio for both the risk of developing cognitive decline and impairment with the use of “highest” doses of CNS medication were nearly identical. Therefore, this point estimate is probably the best first approximation of the true magnitude of the association between higher CNS medication doses and cognitive impairment. As an additional limitation, potential confounding by indication attributable to behavioral complications that sometimes occur in older adults with severe cognitive impairment (i.e. dementia) could not be controlled for as this information was not collected by the Health ABC study. Finally, this study sample included at baseline only relatively healthy community dwelling older adults living in two states and, therefore, may not be representative of other populations elsewhere.