Assessing Antidepressant Safety in the Elderly

Although evidence shows that selective serotonin reuptake inhibitor (SSRI) antidepressants cause less orthostasis and interfere less with psychomotor function than do tricyclic antidepressants (TCAs), a recent pharmacoepidemiologic study found them comparable in increasing elderly patients' risk for falling (Thapa et al., 1998). For patients also receiving multiple cardiovas-cular medications, however, the study did substantiate a lower risk for falls with SSRIs relative to TCAs.

The study was a retrospective analysis of the records of 180 days of treatment for 2,428 nursing home residents who were either antidepressant nonusers or had newly prescribed antidepressants (665 received TCAs or other heterocyclic antidepressants, 612 SSRIs and 304 received trazodone [Desyrel]).

In the 1,460 person-years studied, 3,524 falls were documented. The elderly institutionalized patients receiving SSRIs were found to have had 80% more falls, and those receiving a TCA had twice the number of falls, than did matched patients not receiving an antidepressant. These findings are consistent with a study published earlier that found no significant difference between TCAs and SSRIs in the associated increased rates of hip fractures subsequent to falls (Liu et al., 1998).

These studies implicate the different antidepressant classes with a similarly heightened risk of elderly patients falling. More important, they illustrate the disparities between drug responses observed in the elderly and those assumed to occur from studies with younger adults. In an editorial accompanying the Thapa et al. study, Jerry Avorn, M.D., of the Harvard Medical School, noted that conventional trials conducted against placebo in younger patients can provide sufficient information to approve an antidepressant for the market. But, he added, "It leaves the practitioner hungry for more clinically relevant data, which may be very difficult to find" (Avorn, 1998).

Drug studies that are conducted with younger adults are difficult to apply to the elderly because of differences in drug disposition and response, and the greater susceptibility of the elderly to side effects. "How might a drug's effect change when it is used in older patients, particularly frail ones?" Avorn asked. "Its risks may be higher, its efficacy lower."

The pressing need for depression treatment studies to be conducted in the elderly is evident from the high prevalence of depression in this age group that can be responsive to appropriate antidepressanttreatment (NIH, 1991), and the increased mortality associated with untreated depressive symptoms. In a study conducted by the Osteoporotic Fractures Research Group published in the October 1998 Archives of Internal Medicine, elderly women with six or more symptoms of depression had a 24% mortality rate over seven years. A matched sample with no depressive symptoms had a 7% mortality rate over the same period, and those with three to five symptoms had a 17% rate (Whooley and Browner, 1998). Adjusting for potential confounding factors such as history of myocardial infarction, stroke or diabetes, the investigators found depressive symptoms correlated with an increased risk of death from cardiovascular diseases and noncancer, noncardiovascu-lar diseases, but not with deaths from cancer.

Clinical data from depression studies in the elderly can guide effective antidepressant treatment and monitoring to reduce morbidity and mortality from both the depressive disorder and from adverse reactions to the medication. Such data are anticipated, for example, from the first clinical trial of an antidepressant in the treatment of depression in patients 75 years of age and older, now being conducted with citalopram (Celexa) in 200 patients in 10 centers in the United States. In addition to multiple instruments to gauge antidepressant efficacy, the drug safety in this trial is being determined through adverse event monitoring, laboratory measurements, physical examination, and vital sign and electrocardiogram monitoring. This trial will also include magnetic resonance imaging of each patient at baseline.

Factoring Falls

Purushottam B. Thapa, M.S., M.P.H., and colleagues from the division of pharmaco-epidemiology, department of preventive medicine at Vanderbilt University School of Medicine in Nashville, Tenn., identified their study cohort from computerized records of two pharmacies consulting with 80 nursing homes. They approached the 55 facilities having the most frequent use of SSRIs. Of those, 54 agreed to participate and 53 had records of adequate quality.

Patients over 65 years of age were identified as new users of antidepressants when beginning the medication for other than somatic symptoms such as migraine, after a period of at least 90 days without antidepressant medication. Nonuser controls were randomly selected from residents meeting all other criteria for cohort eligibility. The number of falls during the study period were ascertained from incident reports and medical records.

The baseline characteristics of the antidepressant user and nonuser groups were distinctly different. Relative to the nonusers, those using antidepressants had greater mobility, greater use of psychotropic and other types of drugs, and roughly twice as many falls in the 90-day lead-in period, which suggested a greater baseline risk for falls. Considering the possibility that the depression or its correlates, rather than the antidepressants, might increase the rate of falls by increasing the level of disability, the investigators controlled for an extensive set of reasons for baseline impairment, but found the correlation with antidepressants persisted.

Using Poisson regression models to adjust rate ratios of falling for the subjects' characteristics (such as age, sex, body-mass index, ambulatory status and previous falls, incontinence, cognitive impairment, use of physical restraints and use of certain other medications including anticonvulsants, antipsychotics and sedatives) the investigators determined that the rate ratio of falls relative to nonusers was highest with TCAs at 2.0, followed by 1.8 with SSRIs and 1.2 with trazodone. The rate of falls with TCAs and SSRIs increased with increased daily dosage.

Recognizing that cardiovascular disease can increase the severity of orthostasis caused by TCAs, Thapa and colleagues also assessed the rate of falls in relation to the number of cardiovascular medications being taken. The 2.0 rate ratio of falls with TCAs in patients taking no cardiovascular medications rose to 3.3 in patients taking three or more. There was, however, no such increased rate of falling with an increased number of cardiovascular medication taken by users of either SSRIs or trazodone. Thus, the little difference between the rate of falls occurring with TCAs and SSRIs in patients who did not receive cardiovascular medications grew substantially to favor the safety of SSRIs in elderly patients on multiple cardiovascular medications.

Avorn pointed out some methodological difficulties inherent in such an observational study. Since the antidepressants were not randomly assigned, for example, the SSRIs might have been prescribed to those patients who were deemed at most risk for falling, under the assumption that the SSRIs contribute less to the risk. In addition, reliance on the documentation procedures in the nursing home is likely to be less accurate than outcome monitoring in a prospective study. "If an elderly person falls in a nursing home and no one records it," Avorn posed, "does it still make a sound in the database?"

Despite such methodological limitations, Avorn found the conclusions to be validly drawn. While the SSRIs pose less risk than TCAs for causing falls in the frail elderly who are receiving cardiovascular medications, both the SSRIs and TCAs are associated with a dose-dependent increased risk of falls in the elderly in general. Elderly patients receiving these antidepressants should, therefore, be appropriately monitored, assisted and advised to stand and ambulate with care.

The "fear of falling," however, should not preclude appropriate antidepressant treatment that can avert the morbidity and mortality of depressive illness.

References:

References

Avorn J (1998), Depression in the elderly--Falls and pitfalls. N Engl J Med 339(13):918-920.

Liu B, Anderson G, Mittmann N et al. (1998), Use of selective serotonin reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 351(9112):1303-1307.

NIH Consensus Development Panel in Depression in Late Life (1993), Diagnosis and treatment of depression in late life. Psychopharmacol Bull 29(1):87-100.

Thapa PB, Gideon P, Cost TW et al. (1998), Antidepressants and the risk of falls among nursing home residents. N Engl J Med 339(13):875-882. See comments.

Whooley MA, Browner WS (1998), Association between depressive symptoms and mortality in older women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 158(19):2129-2135.