Within the highest benzodiazepine category (≥121 TSDDs), the median level of use was 375 TSDDs (equivalent to slightly over a year of daily use). Table 2 ⇑ shows participants’ characteristics overall and by cumulative benzodiazepine exposure in the 10 years before study entry. The median age of participants at study entry was 74, 91% (n=3134) were white, 60% were women, and most (66%) had some college education. The most common benzodiazepines were temazepam, diazepam, clonazepam, triazolam, and lorazepam (table 3 ⇓ ), which together accounted for 83% of the benzodiazepine exposure. Participants with heavier benzodiazepine use were more likely to be women and report fair or poor self rated health, have more depressive symptoms, and have comorbidities (such as hypertension, stroke, and coronary heart disease) than non-users. Overall, 30% had filled at least one prescription for a benzodiazepine in the 10 years before study entry, though lonely 3% (n=98) had recently used a benzodiazepine (within six months).
We hypothesized that higher cumulative use would be associated with increased risk. We used data from a prospective cohort study with research quality diagnoses of dementia and computerized pharmacy data to evaluate the association between cumulative benzodiazepine use and the risk for dementia and cognitive decline.
Drug use was ascertained from Group Health’s computerized pharmacy data and included drug name, strength, route of administration, date dispensed, and amount dispensed. Few participants, however, used non-benzodiazepine hypnotics. The exposure included benzodiazepines and non-benzodiazepine hypnotics that bind to the gamma-aminobutyric acid (GABA) receptor, such as zolpidem, zaleplon, and eszopiclone.
Because of this, there is a non-linear relation between the score and underlying cognitive ability, resulting in imprecision at the higher end of the scale. A feature of this score is that the distribution of item difficulty is not uniform across levels of cognitive ability. For example, there are few hard questions that would be appropriate for those with no cognitive impairment. We used the CASI score for our primary analyses of cognitive trajectory. 23 This deals with the relative insensitivity of the CASI to detect cognitive decline in people with high cognitive functioning. 22 We therefore performed secondary analyses after applying item response theory (IRT) methods to generate CASI-IRT scores, which have linear scaling properties (Parscale, Scientific Software International, Chicago, IL).
Participants were assessed at study entry and biennially thereafter to evaluate cognitive function and collect demographic characteristics, medical history, health behaviors, and health status. The original cohort of 2581 people was enrolled in 1994-96 and 811 additional participants in 2000-03. For the analyses of cognitive trajectory, we included all participants who had a valid cognitive score at baseline. For the analyses of dementia, we required participants to have at least one follow-up visit. 18 Briefly, participants aged ≥65 without dementia were randomly sampled from Group Health members in the Seattle area. Because we were interested in whether benzodiazepine use was associated with a more rapid cognitive decline only in participants who had not yet had a diagnosis of dementia, we excluded from these analyses any visits made after the date of onset of dementia. In 2004 the study began continuous enrollment to replace those who developed dementia, died, or dropped out. Study procedures have been reported elsewhere. The Adult Changes in Thought study is a population based prospective cohort study conducted within Group Health, an integrated healthcare delivery system in the north west US. Our analyses were limited to participants who had at least 10 years of prior membership of Group Health at enrollment to ensure adequate data on long term exposure to medication (fig 1 ⇓ ).
No association was found with the highest level of benzodiazepine use (≥121 TSDDs) for dementia (hazard ratio 1.07, 95% confidence interval 0.83 to 1.37) or Alzheimer’s disease (0.95, 0.71 to 1.27) compared with non-use. Findings for Alzheimer’s disease were similar. The 3434 participants included in these analyses accrued 25 019 person years of follow-up, with a mean of 7.3 (SD 4.8) years. Table 4 ⇓ shows the follow-up time and number of events according to exposure categories. When we split the highest category of benzodiazepine use into two groups, the hazard ratio for dementia was 1.11 (0.78 to 1.58) for 121-364 TSDDs and 1.03 (0.73 to 1.44) for ≥365 TSDDs. Relative to non-use, there was a slightly increased risk for dementia for participants with low (1-30 TSDDs; 1.25, 1.03 to 1.51) or moderate use (31-120 TSDDs; 1.31, 1.00 to 1.71); whereas for Alzheimer’s disease, increased risk was noted only among participants with low use (1.27, 1.03 to 1.57). Figure 3 ⇓ shows age adjusted and multivariable adjusted hazard ratios for dementia and Alzheimer’s disease associated with cumulative benzodiazepine use. During this time, 797 (23.2%) participants developed incident dementia, of whom 637 (79.9%) developed Alzheimer’s disease.
In additional models, we included depressive symptoms as a time varying covariate and adjusted for the Charlson comorbidity index (Deyo adaption). 9. Given the uncertainty regarding when prodromal symptoms might first emerge before a diagnosis of dementia, we extended the lag time to two years. For the dementia analyses, we performed several sensitivity analyses to explore the robustness of our results. 33 Lastly, we performed a post hoc analysis extending the lag time to five years to replicate the methods used by another study.
Design Prospective population based cohort.
No patients were involved in setting the research question or the outcome measures, nor were they involved in recruitment or the design and implementation of the study. There are no plans to involve patients in the dissemination of results.
Conclusion The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.
20 21 The date of onset of dementia was assigned as the midpoint between the study visit that triggered the evaluation of dementia and the preceding visit. We used the cognitive abilities screening instrument (CASI) to screen for dementia at study entry and at each biennial study visit. 19 Scores range from 0 to 100, with higher scores indicating better performance. Participants with scores of ≤85 underwent a standardized diagnostic evaluation for dementia, including a physical and neurological examination and neuropsychological testing. The diagnoses of dementia and Alzheimer’s disease were made with standard research criteria. The results, along with clinical data from participants’ medical records, were then reviewed in a multidisciplinary consensus conference including the examining physician, a neuropsychologist, another study physician, and the study nurse. Participants with new onset dementia underwent at least one follow-up examination to confirm the diagnosis.
First, cumulative benzodiazepine use was calculated in the 10 years immediay before each study visit (that is, no one year lag) as we were evaluating cognitive decline only in participants who had not yet had a diagnosis of dementia. Second, we created a measure of recent use defined as filling two or more prescriptions for a benzodiazepine in the six months before each visit, requiring each prescription to have at least seven TSDDs (fig 2 ⇑ ). Our exposure for the analyses of cognitive trajectory differed in a few ways from the one we defined for analyses of dementia.
The most recent year was excluded because of possible use for prodromal symptoms. Analyses of cognitive trajectory used linear regression models with generalized estimating equations. Incident dementia and Alzheimer’s disease were determined with standard diagnostic criteria. Multivariable Cox proportional hazard models were used to examine time varying use of benzodiazepine and dementia risk. Main outcomes measures The cognitive abilities screening instrument (CASI) was administered every two years to screen for dementia and was used to examine cognitive trajectory. Benzodiazepine exposure was defined from computerized pharmacy data and consisted of the total standardized daily doses (TSDDs) dispensed over a 10 year period (a rolling window that moved forward in time during follow-up).
We used a working independence correlation matrix and calculated standard errors using the Huber-White sandwich estimator to account for the correlation between multiple CASI scores from the same individual. 32 We estimated the average difference in rate of cognitive decline, defined as decline in CASI per year, between user groups by including an interaction term between age at follow-up and level of cumulative exposure. Models adjusted for the same covariates as in the dementia analyses. We evaluated the average differences in CASI scores and the average differences in rates of decline of these scores between benzodiazepine user groups using linear regression models estimated via generalized estimating equations. Analyses of the association between CASI trajectory and recent benzodiazepine use (six months before visit) also adjusted for cumulative use (six months to 10 years before visit).
Minimum effective daily dose for benzodiazepines.
Single dose studies have shown that benzodiazepines impair aspects of cognition (such as memory and attention). 5 It remains uncertain whether long term use is associated with global cognitive decline. Given the enormous public health implications, we need a better understanding of the potential cognitive risks of cumulative benzodiazepine use. Two of these reported an increased risk of dementia with benzodiazepine use, 8 9 while the other did not. 8 9 10 11 12 13 14 Examination of this relation is challenging because dementia can be preceded by symptoms such as insomnia, anxiety, and depression, 15 16 17 which are often treated with benzodiazepines. 6 7 Considerable attention has focused on the potential relation between benzodiazepines and increased risk of dementia. Observational studies must use appropriate design strategies to account for benzodiazepines used to treat early symptoms of dementia to avoid bias from reverse causation. 14 These studies had limitations including lack of information about duration and dose of benzodiazepine treatment 8 and the reliance on administrative data to identify people with Alzheimer’s disease. We are aware of three studies that intentionally considered the prodromal phase and potential for reverse causation. Some well conducted studies suggest that long term use does not increase the risk of cognitive decline, but results are conflicting. 9 14 No studies have been conducted in the US, where patterns of benzodiazepine use differ from other countries.
Association between incident dementia and Alzheimer’s disease and six year cumulative benzodiazepine use with five year lag time.*† Figures are hazard ratios (95% CI).
All analyses were performed with SAS version 9.2 (SAS Institute, Cary, NC).
Higher benzodiazepine use was not associated with more rapid cognitive decline. For dementia, the adjusted hazard ratios associated with cumulative benzodiazepine use compared with non-use were 1.25 (95% confidence interval 1.03 to 1.51) for 1-30 TSDDs; 1.31 (1.00 to 1.71) for 31-120 TSDDs; and 1.07 (0.82 to 1.39) for ≥121 TSDDs. Results Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed Alzheimer’s disease. Results were similar for Alzheimer’s disease.
Fig 1 Sample for analyses of dementia and cognitive trajectory in Adult Changes in Thought (ACT) study.
Demographic factors included age, sex, and years of education. Information about covariates came from standardized questionnaires administered at each study visit and from Group Health’s electronic databases. 31. 30 We ascertained presence of several comorbidities including hypertension or diabetes mellitus treated with drugs (computerized pharmacy data), history of stroke (self report or electronic databases), and coronary heart disease (self report). 29 Participants were asked about smoking, exercise, and self rated health. Body mass index (BMI) was determined from measured height and weight. Symptoms of depression were obtained from the short version of the Center for Epidemiologic Studies Depression scale.
Characteristics of participants at study entry, overall and by prior cumulative benzodiazepine use.* Figures are numbers (percentage) of particpants.
Benzodiazepine use was not significantly associated with Alzheimer’s disease at any exposure level. For dementia, there was a modestly increased hazard ratio between 1.1 and 1.4 for ≤90 TSDDs but risk declined toward 1.0 with higher exposure. These curves show the estimated hazard ratios (and 95% confidence intervals) for each level of exposure relative to a reference group with no cumulative exposure (0 TSDDs). Figure 4 ⇓ shows results from additional analyses that modeled benzodiazepine exposure as a continuous variable with natural cubic splines.
There were two rounds of recruitment and followed by continuous enrollment beginning in 2004. Participants 3434 participants aged ≥65 without dementia at study entry.
Follow-up time and number of events according to exposure category.
Adjustment for depressive symptoms as a time varying covariate or for overall comorbidity did not alter estimates appreciably. In the post hoc analysis with a five year lag, we continued to find no association between cumulative benzodiazepine use and dementia (table 5 ⇓ ). When we extended the lag time to two years, the associations for the lowest level of benzodiazepine use were no longer significant for either dementia (hazard ratio 1.18, 95% confidence interval 0.97 to 1.44) or Alzheimer’s disease (1.18, 0.95 to1.47) (fig 3).
Multivariable models adjusted for study cohort, age at study entry, sex, educational level, hypertension, diabetes mellitus, current smoking, stroke, coronary heart disease, BMI, regular exercise, self rated health, and depressive symptoms. Fig 3 Hazard ratios for all cause dementia and Alzheimer’s disease for each level of cumulative benzodiazepine exposure compared with no use.
Fig 4 Association between cumulative benzodiazepine use modeled as spline and risk of incident dementia or Alzheimer’s disease.
Objective To determine whether higher cumulative use of benzodiazepines is associated with a higher risk of dementia or more rapid cognitive decline.
28 Figure 2 ⇓ shows how exposure windows were defined. 24 For each participant, we summed the SDDs for all filled prescriptions for benzodiazepines during the 10 year exposure window to create a cumulative total standardized daily dose (TSDD). This level of use could be achieved by daily use for 121 days or could represent episodic use over several years. At each time point during follow-up, the cumulative exposure for all participants at risk is recalculated by summing all of their benzodiazepine use in the previous 10 years (after exclusion of the most recent year ). 25 26 27 We constructed a time varying measure defined as the TSDD dispensed over a 10 year window after excluding dispensings in the most recent year, which could have been for prodromal symptoms of dementia. To create our exposure measures, we first calculated the total benzodiazepine dose for each prescription by multiplying the drug strength and the number of tablets dispensed. As examples, a person would reach the highest level of exposure in a 10 year period if he/she took any of the following for a total of 121 days or longer: temazepam 15 mg/day, triazolam 0.125 mg/day, or lorazepam 2 mg/day. We categorized cumulative use as no use, 1-30 TSDDs, 31-120 TSDDs, or ≥121 TSDDs based on the distribution of the exposure and clinically meaningful cutpoints. We then calculated a standardized daily dose (SDD) by dividing the product by the minimum effective dose per day recommended for use in older adults (table 1 ⇓ ).
Setting Integrated healthcare delivery system, Seattle, Washington.
1. 1 3 Because of these risks benzodiazepines are not recommended for treatment of insomnia, agitation, or delirium in older adults, and it is recommended that use, if any, be short term. 4 Nonetheless, benzodiazepine use increases with age, and older adults are more likely to use these drugs long term. 1 2 These drugs are associated with many deleterious effects, including falls, fractures, traffic incidents, and delirium. Benzodiazepines are widely prescribed to treat insomnia and anxiety, with about 9-12% of older adults in the United States reporting use.
We hypothesized that cumulative drug exposure, particularly heavier exposure that might accumulate over a long time period (via either intermittent or sustained use), was the most plausible causal mechanism by which use might increase the risk of dementia. Previous studies have not delineated what pattern of benzodiazepine exposure might be important for increasing risk of dementia (for example, long term sustained use versus several episodes of periodic use). We therefore selected a 10 year window based on this hypothesis and on methodologic and practical considerations.
Any and cumulative benzodiazepine use during study period*
We excluded observations with missing covariate information (n=130). In secondary analyses, we modeled the exposure as a continuous variable using natural cubic splines to examine whether results were influenced by the cutpoints chosen for exposure categories. We assessed the assumption of proportional hazards by testing the interaction between the exposure and age at follow-up. Age at study entry was taken as start of follow-up. Participants were followed until the earliest of onset of dementia, disenrollment from Group Health, or last study visit before 30 September 2012. We used separate multivariable Cox proportional hazards models with participant’s age as the time scale to estimate hazard ratios and 95% confidence intervals for the association between benzodiazepine use and incident dementia or possible or probable Alzheimer’s disease. We adjusted for age at study entry, sex, educational level, hypertension, diabetes mellitus, current smoking, stroke, coronary heart disease, BMI, regular exercise, self rated health, and symptoms of depression (variables defined in table 2 ⇓ ). We included time varying measures for coronary heart disease and stroke and the values from the baseline visit for all other covariates.
Fig 2 Scheme for exposure definition for dementia and cognitive trajectory analyses. Here, the year immediay before a study visit is not excluded from the cumulative use measure because by design, no participants could have a diagnosis of dementia at the time of a study visit included in these analyses. The most recent year was excluded because of concerns about possible use for prodromal symptoms (shaded area). At each time point during follow-up, the 10 year cumulative exposure for all participants at risk is recalculated by summing all of their benzodiazepine use in the previous 10 years. For analyses of dementia, a rolling 10 year window was used to define our time varying exposures. For analyses of cognitive trajectory, the circle at the far right represents a study visit at which the cognitive test was administered. Recent exposure is defined as use in the six months immediay before the visit.Can ambien cause early dementia?