Background In nursing home residents, the use of tricyclic andother heterocyclic antidepressants is associated with an increasedrisk of falls. The newer selective serotonin-reuptake–inhibitorantidepressants are largely free of the side effects of thetricyclic agents thought to cause falls and so have been hypothesizedto be safer for those at high risk for falls.
Methods We retrospectively identified an inception cohort of2428 nursing home residents in Tennessee who were new usersof tricyclic antidepressants (665 subjects), selective serotonin-reuptakeinhibitors (612 subjects), or trazodone (304 subjects) or nonusersof antidepressants (847 subjects). We ascertained the numberof falls during therapy and during a similar follow-up periodfor nonusers, then calculated the rate ratios for falls withadjustments for an extensive set of potential confounding factors.
Results The new users of each type of antidepressant had higherrates of falls than the nonusers, with adjusted rate ratiosof 2.0 (95 percent confidence interval, 1.8 to 2.2) for tricyclicantidepressants, 1.8 (1.6 to 2.0) for selective serotonin-reuptakeinhibitors, and 1.2 (1.0 to 1.4) for trazodone. The rate ratiosincreased with the daily dose for tricyclic antidepressants,reaching 2.4 (95 percent confidence interval, 2.1 to 2.8) fordoses of 50 mg or more of amitriptyline or its equivalent, andfor the serotonin-reuptake inhibitors, reaching 1.9 (1.7 to2.2) for 20 mg or more of fluoxetine or its equivalent. Theelevated rates of falls persisted through the first 180 daysof therapy and beyond.
Conclusions In this large study of nursing home residents, therewas little difference in rates of falls between those treatedwith tricyclic antidepressants and those treated with selectiveserotonin-reuptake inhibitors. Hence, the preferential use ofthe newer antidepressants is unlikely to reduce the higher rateof falls among nursing home residents taking antidepressants.
Mood disorders are common among nursing home residents1,2 andare associated with substantial excess morbidity and mortality.3,4,5,6,7,8,9Although major depression is treatable in frail elderly persons,10including nursing home residents,11 there is concern that commonlyused drugs increase the risk of falls and related injuries.12,13Tricyclic and other heterocyclic antidepressants, until recentlythe predominant therapy among elderly patients, produce psychomotorimpairment12 and orthostasis,14,15,16,17 which can lead to falls.13,18In epidemiologic studies of long-term care, users of tricyclicantidepressants have increased rates of falls19,20,21,22 andinjuries,23,24,25 with the increase in risk generally rangingfrom 50 percent to 200 percent. Because residents of long-termcare facilities are very susceptible to falls and related injuries,with rates up to three times those of elderly persons livingin the community,25,26 this possible adverse effect is of majorconcern.
Selective inhibitors of the reuptake of serotonin, effectiveantidepressants largely free of the adverse psychomotor andautonomic effects of tricyclic antidepressants,12,27 may besafer for frail elderly patients at high risk for falls.12,27However, these drugs are expensive and have potentially undesirableeffects in elderly patients.27 We conducted a large inception-cohortstudy to compare directly the rate of falls among new usersof tricyclic antidepressants with that among new users of selectiveserotonin-reuptake inhibitors.
Methods
Cohort
Potential Members of the Cohort
We identified new users of tricyclic antidepressants, selectiveserotonin-reuptake inhibitors, or trazodone and residents whodid not use any antidepressant in an inception-cohort design.We measured the risk factors for falls before the start of antidepressanttherapy, because antidepressant drugs can affect these factors.The study included patients who terminated therapy early becauseof adverse effects of the medication that increased the riskof falls. The cohort was drawn from the computerized recordsof two pharmacy consultants in Tennessee that served a totalof 80 nursing homes. We approached the 55 facilities with themost frequent use of selective serotonin-reuptake inhibitors,of which 54 agreed to participate and 53 had records of adequatequality. For each facility, we then designated a study periodduring which residents were eligible for inclusion in the cohort(the beginning of the period varied from 1993 to 1996, dependingon when we contacted the facility and its retention of records).The length of the study period varied among the facilities.
New Users of Antidepressants
For each resident identified as a new user of antidepressants,we reviewed medication-administration and other records to confirmdrug use and eligibility for the cohort. New users had to havebeen in the facility for 30 days or more (to be reliably identifiedby the consulting pharmacists' monthly records) and to havea qualifying episode of antidepressant use, defined as use thatbegan during the study period and in the facility by a residentat least 65 years of age with no antidepressant use during theprevious 90 days. If there were multiple qualifying episodes,we included only the first.
The analysis in this study was restricted to new users of eithertricyclic or other heterocyclic antidepressants, selective serotonin-reuptakeinhibitors, or trazodone, an atypical antidepressant commonlyused in long-term care because of its sedative properties.27The analysis excluded users of multiple types of antidepressantsand those for whom the primary reason for starting therapy wassomatic (migraine, peripheral neuropathy, or pain).
Nonuser Control Subjects
Nonuser control subjects were randomly selected from among theresidents not taking antidepressants. For logistic efficiency,one nonuser was selected for every pair of new users of antidepressants(stratified according to facility and type of antidepressant).The nonusers were matched to the date of admission (±2years) and the index date (the date antidepressant therapy began)of a randomly selected member of the new-user pair. Nonusershad to meet the same criteria for cohort eligibility on theindex date as the new users.
Follow-Up Period
The follow-up period began on the day after the index date.The follow-up period for new users ended at the time they leftthe facility (because of discharge, death, transfer, or a hospitalstay of more than 14 days) or at the time of cessation of antidepressantuse for more than 14 days, whichever was earlier, and for nonusersit ended at the time they left the facility, at the time theystarted antidepressant use, or at the time the matched new user'sfollow-up ended. The last study day was considered to contributeone half person-day to the follow-up period. Days on which multipletypes of antidepressants or nonstudy antidepressants were usedwere excluded.
Data Collection
Base-line variables for which information was abstracted fromthe nursing home records included the admission date, demographiccharacteristics, current height and weight, ambulatory status,functional status (as defined in the Minimum Data Set28), medicationsand physical restraints used in the previous 7 days, falls inthe previous 90 days, and the primary reason antidepressanttherapy was started (classified as depression or depressivesymptoms, behavioral symptoms of dementia, insomnia, or anxiety,or other or unknown). Insomnia, a symptom of depression, wasclassified separately because it is a common reason for theuse of tricyclic antidepressants in elderly patients. Missingvalues (which never involved more than 2.5 percent of the subjects)were resolved by imputation, with the assumption that data weremissing completely at random.
The use and dose of antidepressants, benzodiazepines, antipsychoticdrugs, and other sedative or hypnotic agents were abstractedfor each day of study follow-up. Doses were converted into equivalentunits on the basis of recommendations for elderly patients.29
Outcome
The primary study outcome was the number of falls during thefollow-up period, ascertained from both nursing home incidentreports and medical records.30 Injurious falls25 were thosethat caused medically treated injuries (fractures, joint dislocationsor sprains, sutured lacerations, or head injuries with alteredconsciousness).
Statistical Analysis
Follow-up for the antidepressant users was classified accordingto the type of drug and the dose taken each day, and univariaterates of falls and rate ratios (with the nonuser control subjectsas the reference group) were calculated. Poisson regressionmodels were used to adjust rate ratios for both base-line characteristicsof the subjects (age, sex, race, time since admission to facility,body-mass index, ambulatory status, number of activities ofdaily living in which the resident was totally dependent oncare providers, incontinence, cognitive impairment, use of physicalrestraints, previous falls, and use of anticonvulsant or antiparkinsoniandrugs) and time-dependent factors (use of benzodiazepines, antipsychoticdrugs, or other sedatives and the number of days since the indexdate [1 to 30, 31 to 90, 91 to 180, or 181 days]). To controlfor coexisting illnesses, we also fitted models with terms forbase-line use of medications, including analgesics, antihypertensivedrugs, other cardiovascular drugs, hypoglycemic drugs, antimicrobialdrugs, antihistamines, bronchodilators, and oral corticosteroids.These terms did not materially affect the estimates, so theywere not included in the final model. There was no evidenceof overdispersion,31 which suggests that the Poisson assumptionwas satisfied. Alternative mixed-effects Poisson regressionmodels that controlled for the inclusion in the analysis ofmultiple falls per resident and effects due to the facilityhad essentially identical findings.
All P values are two-sided. P values for comparisons of adjustedrate ratios were calculated from single-degree-of-freedom contrastswith Wald statistics. All regressions were performed with SASProc Genmod Software (version 6.12, SAS Institute, Cary, N.C.).
Results
Characteristics of the Cohort
The cohort included 2428 elderly nursing home residents, ofwhom 665 were new users of tricyclic antidepressants, 612 werenew users of selective serotonin-reuptake inhibitors, and 304were new users of trazodone; 847 did not use any antidepressants.During the 1460 person-years of study follow-up, members ofthe cohort had 3524 falls (241 per 100 person-years) and 213injurious falls (15 per 100 person-years).
The study cohort was frail and highly impaired (Table 1). Themean age was 82 years, 75 percent were women, 60 percent useda wheelchair or were chairbound or bedbound, 35 percent wereincontinent, 22 percent had major cognitive impairment, 24 percenthad been physically restrained in the previous seven days, and26 percent and 20 percent, respectively, used benzodiazepinesor antipsychotic drugs at base line. In the 90 days precedingthe index date, the members of the cohort had a mean numberof falls of 0.8.
The base-line characteristics of the cohort varied markedlywith the use or nonuse of antidepressants (Table 1). As comparedwith the nonusers, the users of antidepressants had greatermobility, increased use of psychotropic and other types of drugs,and roughly twice as many falls in the previous 90 days, suggestinga greater base-line risk of falls.25,32,33,34 The users of antidepressantswere less likely to be black, had been admitted more recentlyto the facility, and had a lower prevalence of major cognitiveimpairment. As compared with the users of tricyclic antidepressants,the users of selective serotonin-reuptake inhibitors had beenadmitted to the facility more recently, had a lower prevalenceof major cognitive impairment, and had a lower frequency ofphysical restraint. The users of trazodone had been admittedmore recently, had a greater prevalence of major cognitive impairment,and were more likely to have used psychotropic drugs than theusers of tricyclic antidepressants.
The primary reason for starting antidepressant therapy differedaccording to the type of drug. Depression or the occurrenceof depressive symptoms was the primary indication for 55 percentof the users of tricyclic antidepressants, 74 percent of thosewho used selective serotonin-reuptake inhibitors (P<0.001for the comparison with tricyclic agents), and 34 percent ofthose who used trazodone (P<0.001 for the comparison withtricyclic agents); behavioral symptoms of dementia were theprimary indication for 18 percent, 11 percent, and 23 percent,respectively; insomnia or anxiety for 16 percent, 3 percent(P<0.001), and 36 percent (P<0.001); and other or unknownindications for 10 percent, 11 percent, and 8 percent.
The antidepressant drugs were used at relatively low doses.By day 7 of therapy, the mean daily doses were 37 mg of amitriptylineor its equivalent for those using tricyclic agents, 16 mg offluoxetine or its equivalent for those using selective serotonin-reuptakeinhibitors, and 53 mg of trazodone for those using that drug.
Rates of Falls According to Type of Antidepressant
The users of each of the three types of antidepressants hada higher rate of falls than the nonusers, even after adjustmentswere made for differences in potential confounding factors (Table 2).The rate was highest for the users of tricyclic antidepressants,who had an adjusted rate ratio of 2.0 (95 percent confidenceinterval, 1.8 to 2.2). This was significantly greater than therate ratios of 1.8 (1.6 to 2.0, P=0.001) for the users of selectiveserotonin-reuptake inhibitors and 1.2 (1.0 to 1.4, P<0.001)for the users of trazodone. Within each group, there were nosignificant differences between the users of individual drugs.For injurious falls, the adjusted rate ratios were greater than1.0 for the users of each of the three types of antidepressants— 1.3 (95 percent confidence interval, 0.9 to 1.9) forthose using tricyclic antidepressants, 1.7 (1.2 to 2.5) forthose using selective serotonin-reuptake inhibitors, and 1.1(0.7 to 1.8) for those using trazodone — but the confidenceintervals for the tricyclic agents and trazodone included 1,and there were no statistically significant differences amongthe rate ratios.
Table 2. Rate of Falls According to Type of Antidepressant and Specific Drug.
For the users of tricyclic and selective serotonin-reuptake–inhibitorantidepressants, the rate of falls increased with increasingdaily doses of the drug (Table 3). The adjusted rate ratio forthe users of tricyclic agents as compared with the nonuserswas 1.2 for those who used 10 mg or less of amitriptyline orits equivalent and 2.4 for those who used more than 50 mg (P<0.001by the test for linear trend). For the users of selective serotonin-reuptakeinhibitors, the adjusted rate ratio was 1.5 for those who usedless than 20 mg of fluoxetine or its equivalent and 1.9 forthose who used 20 mg or more (P<0.001). However, for theusers of trazodone, those who used less than 50 mg had a higherrate of falls than those who used 50 mg or more.
Table 3. Rate of Falls According to Dose of Antidepressant.
The elevated rates of falls for users of antidepressants persistedover the course of therapy (Figure 1). The residents who receivedtricyclic agents or selective serotonin-reuptake inhibitorsfor more than 180 days (as compared with nonusers with similarduration of follow-up) had adjusted rate ratios of 2.0 and 1.9,respectively; these rate ratios were not significantly different(P>0.05) from those for the first 30 days of therapy (2.5and 2.1, respectively). Within each period, the rate ratioswere highest for the users of tricyclic antidepressants andlowest for the users of trazodone.
Figure 1. Adjusted Rate Ratios for Falls According to the Number of Days from the Start of Antidepressant Use.
The rate ratios were adjusted with the Poisson regression model for age, sex, race, time since admission to the facility and since the index date, body-mass index, ambulatory status, number of activities of daily living in which residents were totally dependent on care providers, incontinence, cognitive impairment, use of physical restraints, previous falls, and use of anticonvulsants, antiparkinsonian drugs, benzodiazepines, antipsychotics, and other sedatives. The data were plotted at the midpoint of the classification intervals of 1 to 30, 31 to 90, 91 to 180, and >180 days for the number of days since the index date. The reference category for all comparisons is nonusers of antidepressants with similar lengths of follow-up. For users of tricyclic antidepressants, selective serotonin-reuptake inhibitors, and trazodone and for nonusers, the respective numbers of person-years were as follows: 1 to 30 days since the index date, 48, 44, 22, and 62; 31 to 90 days, 79, 63, 31, and 94; 91 to 180 days, 92, 60, 34, and 100; and >180 days, 244, 160, 89, and 238. I bars indicate the upper bounds of the 95 percent confidence intervals. The dotted line represents a rate ratio of 1.0, or no difference from nonusers.
The rate of falls varied according to the primary reason antidepressanttherapy was started. For each type of antidepressant, the residentswho began taking the drug for behavioral symptoms of dementia(adjusted rate ratios: users of tricyclic antidepressants, 2.4[95 percent confidence interval, 2.1 to 2.7]; users of selectiveserotonin-reuptake inhibitors, 2.3 [2.0 to 2.7]; and users oftrazodone, 1.4 [1.1 to 1.7]) had higher rates of falls thanthose who began therapy for depression or depressive symptoms(rate ratios of 1.8 [95 percent confidence interval, 1.6 to2.0], 1.7 [1.6 to 1.9], and 1.1 [0.9 to 1.3], respectively;P<0.001 for the users of tricyclic agents and selective serotonin-reuptakeinhibitors; P=0.03 for the users of trazodone). The residentswho began taking antidepressant drugs for insomnia or anxietyhad the following adjusted rate ratios for falls: 2.4 (95 percentconfidence interval, 2.1 to 2.8) for the users of tricyclicagents, 1.8 (1.3 to 2.4) for the users of selective serotonin-reuptakeinhibitors, and 1.2 (1.0 to 1.4) for the users of trazodone.
We assessed the effect of excluding potentially atypical residentsfrom the cohort: those who were chairbound or bedbound, whostarted antidepressant therapy for insomnia or anxiety, or whowere receiving very low doses of antidepressants. None of theseexclusions materially changed the primary findings (Table 4).
Because cardiovascular disease increases the severity of orthostasiscaused by tricyclic antidepressants,35 we assessed the rateof falls according to the base-line use of cardiovascular medications(Table 4). For the users of tricyclic antidepressants, the adjustedrate ratios were 1.8 for those taking no cardiovascular medicationsand 3.3 for those taking three or more medications (P<0.001).In contrast, there was no such trend for the users of selectiveserotonin-reuptake inhibitors. Thus, there was no significantdifference between the adjusted rate ratio for the users oftricyclic agents and that for the users of selective serotonin-reuptakeinhibitors taking no more than one cardiovascular medication;however, the users of tricyclic agents had a greater rate offalls if they took two (P<0.001) or three or more (P<0.001)cardiovascular medications. The rate of falls among the usersof trazodone did not vary according to base-line use of cardiovascularmedications.
Discussion
Our primary objective was to compare the relative safety oftricyclic and selective serotonin-reuptake–inhibitor antidepressantswith regard to falls, a critical end point for frail elderlypatients. When the study began, several reports had shown thatolder users of tricyclic antidepressants had increased ratesof falls and related injuries,19,20,21,22,23,24,25 which wasconsistent with the pharmacologic properties of such antidepressantsand studies of surrogate end points.12 However, this associationwas controversial36 because these investigations had not beenspecifically designed to study antidepressants and consequentlyhad small numbers of antidepressant users or limited measurementof potential confounding factors. The introduction and wideuse of selective serotonin-reuptake inhibitors, which are largelyfree of the side effects thought to cause falls among the usersof tricyclic antidepressants, provided the opportunity to addressthis clinical controversy by allowing a direct comparison ofthe rates of falls among the users of the two types of antidepressants.
The study was conducted among nursing home residents for severalreasons. This population has a strikingly high prevalence ofserious mood disorders, at least half of which are not treated.2,9Because nursing home residents also have the greatest vulnerabilityto falls and related injuries,25,26 clarifying the relativepotential of tricyclic and selective serotonin-reuptake–inhibitorantidepressants to cause falls is of major clinical importance.Nursing homes provided several logistic advantages that madeit possible to study efficiently the large number of patientsneeded to detect differences between the drugs. First, nursinghomes are federally required28 to collect detailed informationon the base-line risk factors for falls; second, records ofmedication administration track the type of antidepressantsand the doses actually taken each day; and third, incident reportsand other records provide a log of falls.
Our findings confirmed the association between the use of tricyclicantidepressants and increased rates of falls. After adjustmentswere made for potential confounding factors, the new users ofthese drugs had a rate of falls during therapy that was twicethat of the nonusers of antidepressants. There was a pronounceddose–response relation, and the increased rate of fallspersisted throughout the period of therapy. However, the newusers of selective serotonin-reuptake inhibitors also had arate of falls that was 80 percent higher than that of the nonusers,and the rate increased with increasing dose and persisted throughoutthe period of therapy, although there was some evidence thatthese drugs were safer in the residents with more severe cardiovasculardisease. Our findings are consistent with a recent report suggestingthat both types of antidepressants confer an increased riskof hip fracture,37 although that record-linkage study couldnot adjust for many potential confounding factors.
Our findings thus suggest either that the rate of falls is increasedby the use of tricyclic or selective serotonin-reuptake–inhibitorantidepressants or that this increase is due to depression orits cofactors. Selective serotonin-reuptake inhibitors do notcause impairment as ascertained by most tests of psychomotorfunction and do not produce orthostasis and thus have not beenthought to increase the risk of falls.12 However, one studyreported an increase in postural sway among older patients takingsertraline,38 although this finding was not confirmed in subsequentreports on paroxetine, sertraline, and fluoxetine.39,40
How could depression or its correlates increase the rate offalls? Because depression increases as the level of disabilityincreases,41 we considered the possibility that our findingsreflected base-line differences between the new users and thenonusers of antidepressant drugs. However, our findings persistedafter we controlled for an extensive set of measures of base-lineimpairment, including functional status, cognitive impairment,medical illnesses, use of neurologic or psychotropic medications,and recent history of falls.
Our data are consistent with the hypothesis that a change inthe health of residents of long-term care facilities that occursnear the time antidepressant therapy begins increases the rateof falls. This change could include the depression itself orworsening medical or neurologic conditions. A diagnostic hallmarkof major depression is psychomotor impairment, and clinicalexperience suggests that depressed patients are "accident prone."42,43Psychomotor impairment may be less responsive to therapy thanneurovegetative and cognitive symptoms.44,45 Clinical experiencesuggests that in frail elderly patients, the onset or intensificationof depressive symptoms often accompanies medical or neurologicdeterioration.41 This line of reasoning is supported by thehigher rates of falls among patients for whom behavioral symptoms— indicators of the progression of dementia — werethe primary reasons for starting antidepressant therapy andby the persistence of increased rates of falls throughout theperiod of therapy.
The atypical antidepressant trazodone accounted for 18 percentof the antidepressant use by the cohort. Interestingly, theresidents taking this drug had only a 20 percent increase inthe rate of falls. Although trazodone is not thought to be ahighly effective antidepressant,27 it is strongly sedating andis thus commonly prescribed for agitation or insomnia.46 Indeed,for 59 percent of the trazodone users, behavioral symptoms ofdementia, insomnia, or anxiety were the primary reason for startingthe drug. Thus, differences in the prevalence and severity ofdepression may have accounted for the lower rate of falls amongthe users of trazodone. This possibility is supported by thefact that the 20 percent increase in the rate of falls amongthe trazodone users was identical to that among the users ofvery low doses of tricyclic antidepressants (equivalent to 10mg or less of amitriptyline), which, when given at these doses,have primarily hypnotic effects.46
In summary, our findings suggest that the elevated rates offalls and related injuries among most nursing home residentstaking tricyclic antidepressants would not be materially reducedby the preferential use of selective serotonin-reuptake inhibitors.All nursing home residents receiving antidepressants shouldbe considered at increased risk for falls, and appropriate preventivecountermeasures should be taken.47
Supported in part by a grant from the Centers for Disease Controland Prevention (R49/CCR410144) and by a cooperative agreementwith the Food and Drug Administration (FD-U-000073-11).
Source Information
From the Division of Pharmacoepidemiology, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville (P.B.T., P.G., W.A.R.); Cost Consulting, Nashville (T.W.C.); and Pharmaceutical Consulting Services, Murfreesboro, Tenn. (A.B.M.).
Address reprint requests to Dr. Ray at the Department of Preventive Medicine, Medical Center North, A-1124, Vanderbilt University Medical Center, Nashville, TN 37232.
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181 days]). To control for coexisting illnesses, we also fitted models with terms for base-line use of medications, including analgesics, antihypertensive drugs, other cardiovascular drugs, hypoglycemic drugs, antimicrobial drugs, antihistamines, bronchodilators, and oral corticosteroids. These terms did not materially affect the estimates, so they were not included in the final model. There was no evidence of overdispersion,31 which suggests that the Poisson assumption was satisfied. Alternative mixed-effects Poisson regression models that controlled for the inclusion in the analysis of multiple falls per resident and effects due to the facility had essentially identical findings. 
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